ENDRIN - CiteSeerX

This report contains the collective views of an in-ternational group of experts and does not necessarilyrepresent the decisions or the stated policy of theUnited Nations Environment Programme, the Interna-tional Labour Organisation, or the World HealthOrganization.

Environmental Health Criteria 130

ENDRIN

First draft prepared by Dr G. T. van Esch, Bilthoven,Netherlands, and Dr E. A. H. van Heemstra-Lequin,Laren. Netherlands

Published under the joint sponsorship ofthe United Nations Environment Programme,the International Labour Organisation,and the World Health Organization

World Health OrganizationGeneva, 1992

The International Programme on Chemical Safety (IPCS) is ajoint venture of the United Nations Environment Programme, theIntemational Labour Organisation, and the World Health Organization.The main objective of IPCS is to carry out and disseminate evaluations oftheeffects of chemicals onhumanhealth and thequality of theenvironment.Supporting activities include the development of epidemiological,experimental laboratory, and risk-assessment methods that could produceinternationally comparable results, and the development of manpower inthe field of toxicology. Other activities carried out by IPCS include thedevelopmentof know-how forcoping with chemical accidents. coordinationof laboratory testing and epidemiological studies, and promotion ofresearch on the mechanisms of the biological action of chemicals.

WHO Library Cataloguing in Publication DataEndrin.@nvironmental health criteria ; 1 30)l.Endrin-toxicity 2.Environmental exposure l.SeriesISBN 92 4 l57l30 6 (NLM Classifrcation: WA 240)ISSN 0250-863X

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@ World Health Organization 1992

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92/9416-Vammala-5500

1 .

CONTENTS

SI.JMMARY AND EVALUATION; CONCLUSIONS;RECOMMENDATIONS ..................." ' .. 13

Ll Summary and evaluation "'..'.......... 13

1.1.1 Exposure """""." '. ' . ......" ' .. 131.1.2 Uptake, metabolism, and excretion --.-"'.' 14

1.1.3 Effects on organisms in the environment .'....."'.'..'.""'. 151.1.4 Effects on experimental animals and in vitro...'.."...."'. l5

1.1.5 Effects on human beings ........... .'.."".....' 1'1L.2 Conclusions ............. 18

1.3 Recommendations.............. ..... ' ... ' . 18

IDENTITY, PHYSICAL AND CIMMICAL PROPERTIES,ANALYTICAL METHODS

2.1 ldentity ... ' ...... ' ...""".202.2 Physical and chemical properties .....'.".""""".'.. 2l2.3 Conversion factors ............. ' ..... ' .-"-222.4 Analytical methods ................"..... '22

SOURCES OFHUMAN AND ENVIRONMENTALEXPOSURE ..................... 30

3.1 Natural occurrence .......,..,....."" '. ' . '303.2 Man-made sources .........................30

3.2.1 Production levels and processes, uses ........................... 303.2.1.1 Worldproductionfigures ...........303.2.1.2 Manufacturing processes ....'.."". 3l

ENVIRONMENTAL TRANSPORT, DISTRIBUTION, ANDTRANSFORMATION ............ ...........,....32

4.1 Transport and distribution between media ............................'..' 324.1.1 Ai r . . . . . . . . . . . . . . . . . . . . . . . . . . . . . " " ' . ' . 324.1.2 Water . . . . . . . . . . . . . . . . . . . . . . . . ' . . . . . . . .32

3.

4.3.1 Biodegradation ....... 36

4.24.3

7.

5.3 Occupationalexposureduringmanufacture,formulation,and use .............."". 84

5.3.1 Manufacture and formulation '.".'..."."."' 845.3.2 Application ....""""'."......" 855.3.3 Appraisal of occupational exposure .."".. 87

KINETICS AND METABOLISM ......... 88

6.1 Absorption, distributioq andelimination ........... 886.1.1 Laboratory animals ............ 88

6.1.1.1 Oral administration ..................... 886.1.1.2 Intravenous administration .......... 90

6.L.2 Domestic animals .............. 916.1.3 Humanbeings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936.1.4 Systems in vitro ................. 93

6.2 Biotransformation............. ............ 936,2.1 Experimental animals ........ 936.2.2 Humanbeings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 966.2.3 Microorganisrns................ ..................... 976.2.4 Plans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

EFFECTS ON ORGANISMS IN TIIE EI.IVIRONMENT................ 99

7.1 Microorganisms................... ......... 997.2 Aquatic organisms ........................ 99

7.2.1 Invertebrates ...................... 997.2.2 Fish .............. ...................... 106

7.2.2.1 Acutetoxicity ....... 1067.2.2.2 Short-term toxicity .............. ........1067.2.2.3 Studies of resistance ...........,....... 1147 .2.2.4 Interaction with other chemicals ...................... 1 1 57.2.2.5 Special snrdies ...... 116

7.2.3 Amphibia .....1187.3 Terrestrial organisms .................... 118

7.3.1 Honeybees .........................1187.3.2 Birds ............ ...................... 1 19

7.3.2.1 Acute toxicity ....... 1197.3.2.2 Short-termtoxicity ..................... 1197 .3.2.3 Studies of reproduction .............l2O7 .3.2.4 Interaction with other chemicals ............... ....... l2l7.3.2.5 Special studies ......1217.3.2.6 Behavioural studies ................... 122

7.3.3 Mammals .....1227.3.3.1 Toxic i ty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1227.3.3.2 Studies of resistance ...................123

7.4 Effects in the field .........................1U7.5 Appraisal of effects on organisms in the environment ............. 126

8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO .......T27

Acute toxicity of technical-grade endrin ............ 1278.1.1 Oral administration............. .................... 1278.1.2 Dermal administration ...... 1278.1.3 Parenteral administration ........................ 1278.1.4 Toxicity of metabolites and isomers ....... l3l

8. 1.4. 1 Mammalian metabolites ................................... l3 I8.1.4.2 Isomers .................132

8.1.5 Acute toxicity of formulated material .....I338.1.5.1 Oral and dermal administration ....................... 1338.1.5.2 Inhalation ............. 133

Short-term exposure ...................... 1348.2.1 Oral administration............. .................... 134

8.2.1.1 Mouse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1348.2.1.2 Rar. . . . . . . . . . . . . . . . . . . . . . . .1348.2.1.3 Rabbi t . . . . . . . . . . . . . . . . . . .1358.2.1.4 Dog . . . . . . . . . . . . . . . . . . . . . . .1358.2.1.5 Domestic animals ....................... 136

8.2.2 Inhalation .... 1378.2.3 Dermal administration ...... 137Skin irritation ..........137Reproduction, embryotoxicity, and teratogenicity ................... 1 378.4.1 Reproduction .....................137

8.4.1.1 Mouse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I378.4.1.2 Rat . . . . . . . . . . . . . . . . . . . . . . . .138

8.4.2 Embryotoxicity and rerarogenicity .......... 1388.4.2.1 Mouse ................... 1388.4.2.2 Rat . . . . . . . . . . . . . . . . . . . . . . . .1398.4.2.3 Hamster ................. ..................... 1408.4.2.4 Perinatal behavioural development .................. 14 1

8.4.3 Appraisal of reproductive effects ............142Mutagenicity and related end-points ...................1428.5.1 Effects on microorganisms .............. ........1428.5.2 Pointmutations inmammaliancells ,,.,,.,144

8 . i

8.2

8.38.4

8.5

8.68.7

8.8

8.5.3 Dominant lethal mutations ..."."...".'."""IM8.5.4 Chromosomal and cytogenetic effects . " " ". " " " " "'.'.'... 144

S.5.5 Host-mediated effects........... ".""......".... 1458.5.6 Sister chromatid exchange. ....."...".....'."' 145

8.5.7 Effecs rn Drosophila melanogaster .......' 1458.5.8 Effects on DNA........ ....." ' . i+08.5.9 Appraisal of mutagenicity and related end-points ...." ". 146Long+erm exposwe ............ """-.-'147Carcinogenicity .................. ........'..1478.7.1 Oral administration.............. .."""""'. ' .... '147

8.7.1.1 Mouse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I478.7.1.2 Rat . . . . . . . . . . . . . . . " " " ' . ' 1488.7.1.3 Tumour promotion ...'."'."...""". 150

8.7.2 Appraisal of carcinogenicity ............" ' .." ' .."""""'...... ' . 150

Special studies ...'.... 1518.8.1 Nervous system '.......""..". 151

8.8. 1. 1 Electrophysiological studies."'...".........""""'.. 15 I8.8.1.2 Histopathological studies """...'.1528. 8. 1.3 Neurotransmitter systems ....... "...... " " " ".... ". " " I 528.8.1.4 Appraisal of effecs on the nervous system...'.. 155

8.8.2 Cardiovascular system ..'... 1558.8.3 Effects on liver enzymes ....."".........."".. 156

8.8.3.1 Mouse ""..." '. ' . .".. ' 1568.8.3.2 Rat . . . . . . . . . . . . . . . . . . . . . . . ' 1578.8.3.3 Guinea-pig ............. ....... ' .".. ' ....... 1588.8.3.4 In-vitro srudies .'."'158

8.8.4 Mscellaneous srudies........ .'..'."""""'..... 1598.8.5 Factors that influence toxicity '..'.'.....'....' 159

8.8.5.1 Nutrit ion ............... ...................... 1598.8.5.2 Potentiation .......... 160

EFFECTS ON HI.]MAN BEINGS .,.......162

9.1 Exposure of the general population.... ."".""."'..'1629.1.1 Acute toxiciry '." ' .. ' . ." ' ... ' . ' .1629.1.2 Poisoning incidents "'........162

9.2 Occupational exposure .................. 1659.2.1 Factory workers......... """" 1659.2.2 Dose-response relationships ...............................'.'.... ". 1 679.2.3 Exposures to mixtures ....". 1689.2.4 Appraisal of effects of occupational exposures.........'... 170

IO. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES ... I7I

REF8R8NCES................... ...... r13

ANNEX I Chemical names of endrin and its metabolites ......................21gANNEX II Medical rreatmenr of endrin poisoning...... ......221ANNEX III Management of major status epilepticus in adulrs ................223

RESUME ............226RESITMEN .........234

WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIAFOR ENDRIN

Members

Dr L.A. Albert, Consultores Ambientales Asociados, Xalapa, Veracnrz,Mexico

Dr V. Benes, Department of Toxicology and Reference Laboratory,lnstitute of Hygiene and Epidemiology, Prague, Czechoslovakia

Dr S. Dobson, Institute of Terrestrial Ecology, Monks WoodExperimental Station, Huntingdon, United Kingdom

Dr G.J. van Esch, Bilthoven, Netherlands (Rapporteur)

Dr E.A.H. van Heemstra-Lequin, Laren, Netherlands (Rapporteur)

Dr S.K. Kashyap, National Institute of Occupational Health,Ahmedabad. India

Dr Yu.L Kundiev, Research Institute of Labour Hygiene andOccupational Di seases, Kiev, Ukraine (V ic e - C hair nnn)

Dr Y. Osman, Ministry of Health, Riyadh, Saudi Arabia

Dr H. Spencer, United States Environmental Protection Agency,Washington DC, USA (Chairman)

Dr C. Winder, National Institute of C)ccupational Health and Safety, ForestLodge, New South Wales, Australia

Secretariat

Dr K.W. Jager, Intemational Programme on Chemical Safety, WorldHealth Org anization, Geneva, S witzerland (S ec r e t ary)

Ms B. Labarthe, Intemational Register of Potentially ToxicChemicals, United Nations Environment kogramme, Geneva,Switzerland

Dr T.K. Ng, Office of Occupational Health, World HealthOrganization, Geneva, Switzerland

NOTE TO READERS OF THE CRITERIA MONOGRAPHS

Every effort has been made to present information in ttre Criteriamonographs as accurately as possible without unduly delaying theirpublication. In the interest of all users of the Environmental Health Criteriamonographs, readers are kindly requested to communicate any errors thatmay have occurred to the Director of the Intemational programme onChemical Safety, World Health Organization, Geneva, Switzerland, inorder that they may be included in corrigenda.

* * t (

A detailed data profile and a legal file can be obtained from theIntemational Register of Potentially Toxic Chemicals, palais des Narions,1211 Geneva 10, Switzerland (Telephoneno. 798%ffi or 7985850).

: * * *

The proprietary information contained in this monograph cannotreplace documentation for regisftation pu{poses, because the latter hasto be closely linked to the source, the manufacturing route, and thepwity/impurities of the substance to beregistered. The data shouldbeusedin accordance with paragraphs 82-84 and recommendations paragraph 90of the Second FAO Government Corsultation (1932).

t0

ENVIRONMENTAL HEALTH CRITERIA FORENDRIN

A WHO Task Group on Environmental Health Criteria for Endrin andIsobenzan r"ret at the World Health Organization, Geneva, from23 to27July I 990. Dr K.W. Jager, IPCS, welcomed the participants on behalf of DrM. Mercier, Directorof IPCS, and the threeIPCS cooperating organizations(UNEP, ILO, WHO). The Group reviewed and revised the draft Criteriamonographs and Health and Safety Guides and made an evaluation of therisks to human health and the environment f,rom exposure to endrin andisobenzan.

The first drafts of these monographs were prepared in cooperationbetween Dr E.A.H. van Heemstra-lrquin and Dr G.J. van Esch of theNetherlands. Dr van Esch prepared the second drafts, incorporating thecofirments received following circulation of the first drafts to the IPCScontact points for Envilsrxlsnl4l Health Criteria monographs.

Dr K.W. Jager of the IPCS Central Unit was responsible for thescientific content of the monographs, and Mrs E. Heseltine, St Ifon-sur-YEzdre, France, for the editing.

The fact that Shell Oil Co. made available to IPCS and the Task Groupproprietary toxicological information on their products is gratefullyacknowledged. This allowed the Task Group to base their evaluation onmore complete data.

The effort of all who helped in the preparation and finalization of themonographs is gratefully acknowledged.

Partial financial support for the publication of this Criteria monographwas kindly provided by the United States Department of Health andHuman Services, through a contract from the National Institute ofEnvironmental Health Sciences, Research Triangle Park, North Carolina,USA, a WHO Collaboratins Centre for Environmental Health Effects.

1 1

1. SUMMARY AND EVALUATION; CONCLUSIONS;RECOMMENDATIONS

1.1 Summary and evaluation

1.r.1 Expsure

Endrin is an organochlorine irsecticide which has been used since the1950s agairst a wide range of agricultural pests, mostly on cotton but alsoon rice, sugar-cane, maize, and other crops. It is also used as a rodenticide.It is available commercially as dusts, granules, pastes, and an emulsifiableconcentrate.

Endrin enters the air mainly by volatilization and aerial drift. Ingeneral, volatilization takes place after application to soils and crops anddepends on many factors, such as the organic matter and moisture contentof the soil, humidity, air flow, and the surface area of plants.

The most important route of contamination of surface water is run-offfrom soil. Contamination from precipitation in the form of snow or rain isnegligible. Local contamination of the environment may occw fromindustrial effluents and careless application practices.

The major source of endrin in soil is from direct application to soil andcrops. Endrin can be retained, transported, or degraded in soil, dependingon a number of factors. The greatest retention occurs in soils with a highcontent of organic matter. The persistence of endrin is highly dependentuponlocal conditions; its halflife in soil can range up to l2years.Volatilization and photodecomposition are the primary factors in thedisappearance of endrin from soil surfaces. Under the influence of sunlight(ultraviolet light), the isomer delta-ketoendrin is formed- In intensesummer sun, about 507o of endrin was isomerized to this ketoendrin within7 days. Microbial transformation (in fungi and bacteria) takes place,especially under anaerobic conditiors, to give the same product,

Aquatic invertebrates and fish take up endrin rapidly from water, butexposed fish trarsfened to wrcontaminated water lose the pesticiderapidly. Bioconcentration factors of 14-18 000 have been recorded aftercontinuous exposure. Soil invertebrates may also take up endrin readily.

13

Summary and evaluation ; conclusions; recommendations

The occasional presence oflow levels ofendrin in air and in surfaceand drinking-water in agricultural areas is of little significance from thepoint of view of public health. The only exposure that may be relevant isdietary intake. In general, however, thereported intake levels arefarbelowthe acceptable daily intake of 0.fi)02 mglkg body weight esrablished in1970 (FAO/WHO, 1971).

1.1.2 Uptake, metabolism, and excretion

Unlike dieldrin, its stereoisomer, endrin is metabolized rapidly byanimals, andvery little is accumulated infat incomparison withcompoundsof similar chemical structure.

Both uptake and excretion after oral administration are rapid in rats,and its biological half-life is 1-6 days, depending on rhe dose level. Asteady state, at which the excreted amount equals the daily intake, isreached after 6 days. A sex difference is observed, in that males excreteendrin and metabolites via the bile much faster than females, resulting inless accumulation in male adipose tissue. Rats excrete this compoundmainly in the faeces as endrin , anti-12-hydroxyendrin, and a hydroxylatedendrin derivative within the first 24h (70-7sEo); a third metabolite, 12-ketoendrin, accumulates in tissues. Rabbits excrete 507o of themetabolitesof endrin in urine, whereas inrats only 2Vo are excreted by this route; onlyunchanged endrin is found in the faeces ofrabbits.

Cows administered endrin at 0. I mg/kg of diet for 2 1 days excreted upto 65Vo as metabolites inwine,ZoVo in faeces, partly as unchanged endrin,and3%o in milk, also mainly as endrin. These cows had residue levels of0.003-0.006 mg/litre in milk, 0.001--0.002 mglkg in mear, and 0.02-0.I mg/kg in fat.

Laying herx fed endrin showedresiduelevels (depending on the dosesgiven) of up to 0. I mg/kg in mear, I mglkg in fat, 0.1-O.2 mg/kg in eggs(yolk), 0.4 mg/kg in kidney, and 0.5 mglkg in liver. Excepr in liver andkidney, the residues found were mainly unchanged endrin. About 50% ofthe administered endrin was excreted in faeces, mainly as metabolites.

Inhumanbeings, rats, rabbits, cows, andhens, themajorbiotransformedmetabolite of endrin is anti-12-hydroxyendrin, rogether with its sulfareand glucuronide conjugates. Four other metabolites were found but in onlyminor quantities. Mainly unchanged endrin is found in body tissues and

14

EHC 130: Endrin

milk. After this pesticide was applied to plants, unchanged endrin and twohydrophilic transformation products were identified.

1.1.3 Etfects on organisms ln the environment

The effect of endrin on soil bacteria and fungi is minimal. Dose levelsof 1G-l000mglkg of soilhadno effectondecompositionof organic matter,denitrification, or generation of methane. Endrin is very toxic to fish,aquatic inverteb'rates, and phytoplankton: the 96-h LC, values are mostlybelow 1.0 pgllitre. The lowest observed adverse effect level in a life cycletest on the mysid shrimp, My sidopsis bahia,was established at 30 ng/litre.

Thereported tests on the acute toxicity of endrin in aquatic organismswere conducted in aquaria without sedimenl the presence of sedimentwould be expected to attenuate the effect of endrin. Heavily contaminatedsediment had little effect on species living in open water, suggesting thatsediment-bound endrin has low bioavailability. Tests have not beenconducted on aquatic animals living in sediment.

The LD, for terrestrial mammals and birds is in the order of 1.G-10.0 mg/kg body weight. Mallard ducks fed up to 3.0 mg/kg body weightfor 12 weeks showed no effect on egg production, fertility, or hatchability.

Certain species of aquatic invertebrates, fish, and small mammalshave beenreported to be resistant to the toxicity ofendriq and exposure toseveral different organochlorine pesticides led to selection of strainsresistant to endrin.

Fish kills were observed in areas of agricultural run-off and industrialdischarge; and declining populations of brown pelicans (in Louisiana,USA) and of sandwich tems (in the Netherlands) have been anribured toexposure to endrin in combination with other halogenated chemicals.

1.1.4 Ettects on experimental anlmals and in vitro

Endrin is a highly toxic pesticide, the signs of intoxication beingneruotoxic. The oral LD, of technical-grade endrin for laboratory animalsis in the range of 343 mg/kg body weight; the dermal LDro for rars is 5-20 mg*lg body weight. No substantial difference in acute oral or dermaltoxicity was found between technical-grade and formulated (emulsifiableconcentrate and wettable powder) products.

15


Short-term experiments for oral toxicity have been carried out usingmice, rats, rabbits, dogs, and domestic animals. In mice and rats, themaximumtolerateddoses for6 weeks were 5 and 15 mgAg diet (equivalentto 0.7 mg/kg body weight), respectively. Rars survived a 16-week exposureto i mg/kg diet (equivalent to 0.05 mg/kg body weight); rabbits died afterreceiving repeated doses of I mglkg body weight. In dogs, a dose of 1 mg/kg of diet (approximately equivalent to 0.025 mglkg body weight), givenover 2 years, was without effect.

The newological basis of the observed signs of intoxication is inhibitionof gamma-aminobut5nic acid (GABA) function at low doses. Like otherchlorinated hydrocarbon insecticides, endrin also affects the liver, andstimulation of enzyme systems involved in the metabolism of otherchemicals is evident, as shown by, for instance, decreased hexobarbitalsleeping time in mice.

Doses of 75-150 mglkg applied dermally as a dry powder for 2 h dailycaused convulsions and death in rabbits but did not result in skin irritation.Production of systemic toxicity without irritation at the sire of contact isnoteworthy.

Long-termstudies of toxicity and carcinogenicity have been performedin mice and rats. No carcinogenic effect was found, but these studies hadshortcomings, including poor survival of the animals. The no-observed-effect level for toxicity in a two-year study in rats was I mg/kg of diet(equivalent to about 0.05 mg&g body weight). Tumour promoring effecrswere not demorstrated when endrin was tested in combination withsubminimal quantities of chemicals known to be carcinogenic to animals.The Task Group concluded thar the data are insufficient to indicate tharendrin is a carcinogenic hazard to humans.

Endrin was found to be nonmutagenic in several studies.

In most studies, it was not teratogenic to mice, rats, or hamsters, evenat doses that caused matemal or fetotoxicity. The no-observed-adverse-effect level was 0.5 mg/kg body weight in mice and rars and 0.75 mg/kgbody weight in hamsters. Endrin did not induce reproducrive effects in ratsover three generatiors when given at a dose of 2 mg/kg of diet (about0.1 mg/kg body weight).

16

EHC 13A: Endrin

A number of the metabolites of endrin have similar or higher acutetoxicities than the parent compound, The uansformation product, delta-ketoendrin, is less toxic than endrin, but l2-ketoendrin is considered to bethe most toxic metabolite of endrin in mammals, with an oral LDro in ratsof 0.8-1.1 mglkg body weight.

1.1.5 Effects on human belngs

Several episodes of fatal andnon-fatal accidental and suicidal poisoninghave occurred. Cases of acute non-fatal intoxication due to accidental over-exposure were observed in workers in an endrin manufacturing plant. Theoral dose that causes death has been estimated to be approximately 10 mg/kg body weight; the single oral dose that causes conwlsions was estimatedto be 0.25-1.0 mg/kg body weight.

The primary site of action of endrin is the central nervous system.Exposure of humans to a toxic dose may lead within a few hours to suchsigns and symptoms of intoxication as excitability and convulsions, anddeath may follow within 2-I2 h after exposure if appropriate treatment isnot administered immediately. Recovery from non-fatal poisoning is rapidand complete.

Endrin does not accumulate in the human body to any significantdegree. No long-term adverse effects were reported in 232 occupationallyexposed workers (lengthof exposure, 4-27 years) wrdermedical supervision(observation time,4-29 years). The only effect observed was indirectevidence of a reversible stimulation of drug metabolizing enzymes.

Endrin was detected in virtually none of a large number of samples ofadipose tissue, blood, and breast milk analysed in many countries. TheTask Group attributed the absence of endrin in human samples to the lowexposure of the general population to this pesticide and to its rapidmetabolism.

Endrin was detected in blood (at up to 450 Fgfiitre) and in adiposetissue (at 89.5 mg/kg) in cases of fatal accidental poisoning. No endrin wasfound in workers under normal circumstances, The threshold level ofendrin in blood, below which no sign or symptom of intoxication occurs,has been estimated to be 50-100 pgllitre. The half-life of endrin in bloodmay be in the order of 24h.

t 7


1.2 Conclusions

Endrin is an insecticide with high acute toxicity. It may cause severepoisoning in cases of over-exposure caused by carelesshandling during itsmanufacture and use or by consumption of contaminated food. Thegeneral public is exposed to endrinmainly as its residues infood; however,the reported intake of endrin is generally far below the acceptable dailyintake established by FAOAVHO. Such exposures should nor consrirure ahealth hazard to the general population. When good work practices,hygiene measures, and safety pre€autions are enforced, endrin is unlikelyto present ahazard to exposed workers.

It is clear that rurcontrolled discharges of endrin during its manufacture,formulation, and use can result in acute environmental problems associatedwith its high toxicity. The effects on wildlife of its agricultural use are lessclear, although fish and fish-eating birds are at risk from surface run-off.Declines in the populations of some avian species have treen associatedwith the presence of high levels of residues of various organochlorines inthe tissuesof adults andineggs. Endrinhas beenmeasured in someof thesespecies; however, it is very difficult ro separare the effects of the differentorganochlorines present.

1,3 Becommendations

i. Endrin should not be used unless it is indispensable and only whennoless toxic alternative is available.

2. For the health and welfare of workers and the general population, thehandling and applicationof endrin should be enrrusred only to competentlysupervised, well-trained operators who will follow adequate safety measuresand apply endrin according to good agricultural practices.

3. The manufacture, formulation, agricultural use, and disposal ofendrin should be managed carefully to minimize contamination of theenvironment, particularly surface water,

4. People exposed regularly to endrin should undergo periodic healthevaluations.

5. Epidemiological studies of exposed worker populations should becontinued.

18

EHC 130: Endrin

6. In countries where endrin is still used, food should be monitored forendrin residues.

7. If the use of endrin continues, more information should be obtainedon the presence, ultimate fate, and toxicity of l2-ketoendrin and delta-ketoendrin.

1 9

2. IDENTITY, PHYSICAL AND CHEMICALPROPERTIES, ANALYTICAL M ETHODS

2.1 ldentity

CAS chemical name: (l aa,2B,2aB,3 a,6o',6 aB,7 8,7 au) -3,4,5,6,9.9 -hexachloro I a,2,2a,3, 6,6 a,1,7 a- x,talay dr o -2,7 :3,6 -dimethanonaphth[2,3 -b]ox irene(9Cr-CAS)

1,2,3,4,10,10 -hexachloro-6,7-epoxy-I,4,4a,5,6,7,8,8a-octahydro- 1,4-e ndo,e ndo -5,8-dime&anonaphthalene

lR,4Sy'aS,5S,6S,7R,8R,8aR)-1,2,3,4,1 0,10 -hexachloro-

1,4,4a,5,6,7,8.8a-octahydro-6,7-epoxy-1,4:5,8- dimethanonaphthalene

crrHsclp380.93Endrin72-20-8I0i575000Endrex, Experimental Insecticide 269,Hexadrin, Nendrin, NCI-COO 1 57,ENT17251, OMS 197, and MendrinEndrin

Former CAS chemical name:

ruPAC chemical name:

Chemical structure:

Endrin is the endo,endo stereoisomer of dieldrinEmpirical formula:Relative molecular mass:Commonname:CAS registry number:RTECS registry number:Synonyms:

Trade name:

20

EHC 130: Endrln

Purity: Not less tlvt92vo,Impruities includedieldrin (O.42Vo), aldrin (0.03%),isodrin (O.7 3Vo), endrin half-cageketone (l.57Vo), endrin aldehyde(O.OSVo), and heptachloronorbomene(O.@Vo) @onoso et al., 1979).

2.2 Physlcal and chemical propertles

Table 1. Physical and chemical properties of endrin

Physical state

Colour

Odour

Melting-point

Flash-point

Explosion limits

Specific gravity (density)

Vapour pressure

Solubility in water

Solubility in organicsolvents

Log P octanolAvaterpartition coefficient

Crystalline solid

White to light-tan

Mild chemical

226-230'C (decomposes at above 245 "C)

None (dry powder is non-flammable, butcommercial solutions contrain inflammableliquids wifr flash-poinls as low as 27'C)

Non-explosive

1.64 g/ml at 20 "C

2.7 x 10-7 mmHg at 25 'C (36 pPa at 25 "C)

Practically insoluble (0.23 mg/litre at 25'C)

Sparingly soluble in alcohol and petroleumhydrocarbons; moderately soluble in aliphatichydrocarbons;and quite soluble in solventssuch as acetone, benzene, carbon tehacfiloride,and xylene

5.34

Stability: Technical-grade endrin is stable in storage at ambienttemperatwes. Endrin is stable in formulatiors withbasic reagents, alkaline oxidizing agents, emulsifi ers,

21

2.3

2.4

Identity, physical and chemical properties, analytical methods

wetting agents, and solvents. It isomerizes under theinfluenceof ultravioletlight. It reacts withconcentratedmineral acids, acid catalysts, acidoxidizing agents andactive metals. When mixed with certain catalyticallyactive carriers, endrin tends to decompose; however,most active dust carriers can be deactivated by theaddition of hexamethylenetetramine and form stablemixtures with endrin. When heated to above 20O oC,

endrin undergoes molecular reaurangements to formdelta-ketoendrin, a compound that is less active as aninsectide (IARC, 1974; Donoso et al., 1979).

Gonverslon factors

I ppm = 16 mg/m3 at 20 "Ci mg/m3 = 0.063 ppm at 20 oC

Analytical methods

Most of the analyticalprocedures used since the early 1960s have beenbased on the following steps:

(D extraction using a suitable solvent;(ii) clean-up by liquidfliquid partition followed by column

chromatography;(iii) further separation from co-extractives by gas chromatography

(GC); and(i") quantification wing an electron-capture, coulometric, or Hall

electrolytic detector

General procedures based on these steps are not specific for endrin;therefore, its identity must be confirmed in environmental samples. Thiscan be achieved by chemical derivatization and mass spectrometry (Chau& Cochrane, 1969, l97l; Belisle et al., 1972: Chau, 1974; Safe &Hutzinger, 1979).

Roos et al. (1987) used size exclusion chromatography to clean-uppesticides after extraction with ethyl acetate from fish oils, animal fat,cereals, vegetables, fruit, and liver. The recoveries of endri nwereg}-957o,at a limit of detection of 0.02 mg/kg. This method was found to be adequatefor screening and requires only 157o of the amount of solvents normallyused.

22

EHC 130: Endrin

Giibeli & Clerc (1988) described a relatively simple gas-liquid

chromatography method for the detection and approximate quantificationofchlorinatedpesticidesinethanolicextractsofmedicinalplants(tinctures)'The method was based on extraction with hexane and capillary GCFNi-electron-capture detection. The limit ofdetection forendrin was 0.005 mglkgwith a recovery of 7'l .SVo.

Suzuki et al. (19'14) separated many pesticides from extracts of cropsand soil into different groups by column chromatography prior to thin-layerchromatography toobtainsystematicidentificationanddetermination.Silica gel was used for the column chromatography and for the thin-layerplates; glass columns packed with different absorbents were used for GCseparation. Determination was done using electron-capture detection witha 6Ni source.

To improve the separation by heat of28 organochlorine insecticides,including endrin, using gas-liquid chromatography wiith electron capturedetection, Suzuki & Morimoto (1986) tested three chemically bonded,fused silica capillary columns. The column prepared with OV- 17 performedbest. The method was used with minimal clean-up and gave good resultsintheanalysis ofextractsofseveralsoil samples, avoiding thedisadvantagesoflow resolution ofpeaks in packed columns, handling ofglass capillarycolumns and the high cost of GC-mass spectrometry systems.

Kiang & Grob (1986) developed a screening procedure for thedetermination of 49 pollutants of high priority, including endrin, in soil orsludge. Methylene chloride at two pH values was used in the extractionprocedure, which was followed by capillary GC. No clean-up procedurewas carried out. Separation and identification were performed with a GC-mass spectrometry system involving a 30-m fused silica column; a 60-mcolumn was used for quantification. Recovery of endrin from soil in thebase-neutral extract was 92+ 14Vo from 2.O4 mglkg but only 70+ 87ofrom 20.4 mgftg.

Japenga et al. (1987) described a rapid clean-up procedure for thesimultaneous determination of groups of micropollutants in sediment. Thesamples were pretreated with acid, mixed with silica, and extracted on aSoxtrlet column with a mixture of benzene and hexane. Humic substancesand elemental sulfur were removed by passing the extract through achromatographic column containing basic alumina on which sodiumsulfite and sodium hydroxide were absorbed. After silica fractionation, the

23

Identity, physical and chemical propert'rcs, analytical methods

concentrations of polycyclic aromatic hydrocarbons, polychlorinatedbiphenyls, and ctrlorinated pesticides were determined by GC. The recoveryof endrin was reported to fluctuate between 93 and l03Vo.

The efficiency of clean-up with sulfuric acid and confirmation withpotassium hydroxide-ethanol hydrolysis was studied for 22 organochlorinepesticides and polychlorinated biphenyls in water samples (Hemandez etal., 1987); analysiswasbyGC/electron-capturedetection, andthepesticideswere extracted by partition with lSVo diethyl ether in hexane. After clean-up with sulfuric acid, only 4.9Vo of the endrin was recovered; however,with the potassiumhydroxide-ethanol treatment,9T -lOO7o w asrecovered,depending on the endrin concentration and the length of treatment,

Method 8080 of the US Environmental Protection Agency (EPA)(Manual, SW-M6) was evaluated in a single laboratory study by Lopez-Avila et al. (1988). Since the Florisil clean-up procedure recommendeddoesnotseparateorganochlorinepesticidesfrompolyctrlorinatedbiphenyls,GC analysis on a packed column may result in false identifications;therefore, silica gel was substituted for Florisil, a capillary glass columnwas used instead of the packed column, and a procedure to removeelemental sulfur incorporated. Detection limits for liquid manices rangedfrom 0.02 to 0.09 pgAitre for organocNorine pesricides; for solid matrices,arange of l-6 Fg/kg wasfound Therecovery ofendrininliquid waste wasup to I027o at a spiked concentration of 1.0 pg, but for a sandy loam soilit varied from47 to74%o.

Donahue et al. (1988) compared rwo rechniques for quantifyingenvironmental contaminants in human serum: peak area matching andlinear regression. No statistically signifi,cant difference was seen in theresults obtained by these two methods when the concentration of ctrlorinatedpesticides was > 0.5 pgllire.

The sampling and determination of endrin in air were described indetail by NIOSH (1989).

A method for determining residues of the metabolite anri- l2-hydroxy-endrin, present as the B-glucuronide, in urine was described by Baldwin &Hutson (1980). Following oxidation with sodium metaperiodate andhydrolysis with a mild base, the metabolite is determined by gas-liquidchromatography with electron-capture detection.

24

EHC'130: Endrin

Polychlorinated biphenyls and 21 chlorinated pesticides, includingendrin, were analysed in samples of water, soil, and sediment in sixlaboratories using uniform calibration solutions, analytical methods, andspecial software operating on minicomputers to control the operation of themass spectrometer. The results obtained for solid samples with fourcornbinations of methods for extraction and clean-up were compared;althoughno combinationwas optimal for all samples, shaker andsonicatorextraction, both withFlorisil clean-up, gavethebestresults. Several factorsthat affected the quality of the results were identified, including errors incomputation and transcription and inadequate review of data (Alford-Stevens et al., 1988).

Seventeen laboratories participated in an international comparison ofanalyses for organochlorine compounds (Holden, 1970). The results forendrin, summarized in Table 2, were more variable than those for otherinsecticides. In an inter-laboratory collaborative study reported by aCommittee of the Ministry of Agriculture, Fisheries, and Food of theUnited Kingdom (Anon., I 979) for the derermination of endrin in pork fat(fortified to 0.019 mg/kg), the mean recovery in 1 1 laborarories w as84Vo,but the range was 5-l3lVo.

Table 2. Besults for endrin of an interJaboratory study of the analysis oforganochlorine compounds (Holden, 1 970)

Type of No. of laborator- Mean @ncen- Standard Coefficient Ranoesample ies withresults tration (mg/litre deviation of variation

for endrin or mg/kg)- (%l

Solut ion 17in hexanea

Cod liver 14oi l

Chicken 16egg

Sprat 14

5.929b

0.02

1 .01 17 .1 4.9-8.2

ND.-0.2G

0.07-o.3"

0.09f-0.21

0.136 0.073 54

0.132 0.039 29

"Containing endrin and five other organochlorine insecticidesolrue (nominal, fortified value. 7.0$mo/litrecTwelve laboratories re6orted no deteciable residuedValue reported to be si.rspect"Excluding one.laboratory that reported suspected presence of endrin'tsxcrudrng one taboratory that reported a ,trace'of endrin

25

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Identity, physical and chemical properties, analytical methods

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Thier & Stijve (1986) reported a comparative study among53 laboratories in Switzerland on the analysis of avegetable fat spiked with13 organochlorine and five organophosphorus compounds. Endrin waspresent at a concentration of 0.08 mg&g and was identifiedby 77 Vo of thelaboratories.

Some of the methods that are used for the analysis of endrin aresummarized in Table 3; the estimates given of the accuracy of theprocedures and the limits of detection refer to the specific investigationsand are not absolute values. The percentage recoveries are an indicationof the accuracy of the methods; the precision of individual method is ofinterest particularly in regard to inter-laboratory comparisons,

The many publications on specific procedures are reviewed in theCodex Alimentarius Commission public ation Reco tnme ndatio ns fo rMetlnds of Annlysis of Pesticide Residues,CAC/PR8-1986 (FAOflVHO,1986a). That review lists 14 individual publications; ir also liss thefollowing compendia of methods, which may be consulted.

- Official M ethods of Analysis of the Associatbn of Official AnalyticalChemists, 14th Edition, 1984

- Pesticide Analytical Manual, Washington DC, Food and DrugAdministration

-Manual on Analytical Methods for Pesticide Residues in Foods,Ottawa, Health Protection Branch, Health and Welfare Canada, 1985

-Mbthodensammlung zur Riickstandsanalytik von Pflanzenschutz-mineln (Methods for Analysing Residues of Plant Prorecrion Agents),Weinheim, Verlag Chemie GmbH, 1984

- C he mis try laboratory Guidebo ok,W ashingtonDC, US Deparrmenrof Agriculture

Whatever procedure is adopted should be carried out following therequirements of the Codex Alimentarius Commission publicatton CodexGuidelines on Good Laboratory Practice in Pesticide Residuc Analysis,CAC/PR7-1984 (FAO VHO, 1984).

29

3.1

3. SOURCES OF HUMAN AND ENVIRONMENTALEXPOSURE

Natural occurrence

Endrin does not occur naturally.

3.2 Man-made sources

3.2.1 Production levels and processes, uses

Endrin is a foliar insecticide which acts against a wide range ofagricultural pests at doses of the active material of 0.2{).5 kg/ha. It has abroad spectrum of control and is particularly effective against Lepidoptera.It is usedmainly oncotton but also againstpests of rice, sugar cane, maize,and other crops. It is also used as a rodenticide (IARC, 1974). An endrinemulsion of, 2Voklled4Mo of Achatinafulica snails, an agricultural pest,in India (Singtq 1988).

A general indication of thepossible uses of endrincanbe derivedfromthe maximal residue limits recommended by FAOAMHO (1986b; seesection 10).

3.2.1.1 World production figures

Endrin was developed by J. Hyman & Co. and licensed to bemanufactured by Shell Intemational Chemical Co. and Velsicol ChemicalCo. in 1950 (Thompson, 19?6). It was made in the USA by Shell andVelsicol and in the Netherlands by Shell. Its use has been banned in manycountries and severely restricted inothers @onoso et al., 1979; Gips, 1987;Pearce, 1987). Shell discontinued manufacture of endrin in 1982: it is stillmanufactured in Mexico.

Whetstone (1964) estimated that 2.34.5 million kg of endrin weresold in the USA in 1962. Imports of endrin into Japan in 1970 were72000 kg. The armual quantiries of endrin that were used in paddy riceproduction in Bali over the pericd 1963--'12 varied from 171 to 10 700 kg(Machbub et al., 1988). After 1972, endrin was no longer used.

3A

EHC 130: Endrln

?.2.1.2 Manufacturing process

Endrin is produced by condensing vinyl chloride with hexachloro-cyclopentadiene, dehydrochlorinating the adduct, and subsequent reactionwith cyclopentadiene to form isodrin, which is epoxidized by peracetic orperbenzoic acid (Whetstone, 1964). The intermediate isodrin can bemanufactured via 1,2,3,4,7,7-hexachloronorbomadiene (US EPA, 1985).

3 1

4.1

4.1.1

4.1.2 Water

4. ENVIRONMENTAL TRANSPORT, OISTRIBUTION, ANDTRANSFORMATION

Transport and distribution between media

Air

Endrin can enter the air by volatilization, evaporation, and aerial driftduring application, and as a vaporu from manufacturing and formulatingplants. Most studies showed rapid volatilization following application tosoils and crops, the extent of vaporization depending upon a large numberof factors, including soil organic matter, moistwe content, airhumidity, airflow, and surface area of plants (Donoso et al., 1979).

Endrin can reach surface water by several routes, including effluentsand waste disposal from endrin manufacturing andformulating plants andcareless aerial application, but by far the most important route ofcontamination is surface run-off from soil and crops. Run-off is affectedby numerous, complex factors, such as intensity of precipitation, irrigationpractices, soil permeability, topographic relief, organic content ofthe soil,and the degree of vegetative cover. Soils of low permeability and loworganic content allow copious run-off after heavy precipitation @onosoet al., 1979). Contamination of surface water by industrial effluents andcareless practices and disposal (such a,s washing of drums and sprayequipment in streams) results in regional effects.

In 1961, studies were conducted in the Bayou Yokely basin inLouisiana, USA, where 3300 acres (1335 ha) ofsugar-cane were treatedwith nearly 2000 lb (907 kg) of endrin between June and August. Of18 water samples taken between April and November, six containedendrin at levels of 0.001-O.36 ltgftitre, with an average of 0.1 pgllitre, In1964, the area was treated with 1200 lb(544 kg) of endrin, and thepatternof residues was the same. The mean residue levels in samples taken inSeptember were 0.44 Stgllitrengrab samples and 0.53 pgllitre in carbonadsorption samples; after three months, the average levels were 0.03 and0.M pgnitr", respectively. Sediment samples contained 165 pgTkg; afterthree months, this level had decreased to 70 ttgkg (Lauer et al., 1966).

32

t,,

EHC 130: Endrin

Another, less important source of water contamination is run-off fromendrin-coated seeds. Marston et al. ( 1969) foud that although approximatelyllVo of the initial amount was washed off by water under laboratoryconditions, in field conditions the loss was smaller. The total amountdetected in the watershed 6 days after aerial application of endrin-coatedseed was 0. 12Vo of the applied dose. The highest concentrationfound in thewater was 0.O7 1tgllitre.

A third possible source of contamination is fall-out by precipitation inthe form of rain and snow, but the measrued levels are negligible (seesection 5.I.3.2).

Soil

The major sowce of endrin in soil is from direct application to soil andcrops. The amount of endrin that reaches the soil depends on the type ofcrop and the method of application. The fate of endrin in soil determinesthe degree to which the rest of the environment (water and afinosphere) iscontaminated. hr soil, endrin can be retained, transported, or degraded,depending on a large number of interrelated factors (Donoso et al. , 1979).When endrin was applied to tall, dense crops such as tobacco, no residueappeared in the soil; when it was applied to soil, the amount that remaineddepended on the retentive ability of the soil. Although endrin has strongabsorptive properties in soils such as clay and sandy loam, limited residueswere found. Far greater retention was found in soils with a high organiccontent, in which it was adsorbed quickly and was difficult to remove. Thedegree to which endrin was retained in the soil depended not only on thesoil type but on numerous other factors such as volatilization, leaching,wind erosion, surface run-off, and crop uptake (Harris et al., 1966). Ingeneral, the persistence of endrin is highly dependent upon local conditions,and residue levels can range from traces to milligrams per kilogram. Itshalf-life in soil canbe as long as 12years (Donosoer a1., 1979).

The factors that affect the degree to which endrin is retained in soil(Donoso et al., 1979) can be generalized as follows:

(a) Endrin appears to be less persistent ifit is applied to the soilsurface or to crops rather than being mixed into the soil.

(b) Volatilizationandphotodecompositionaretheprimaryroutesfor the disappearance of endrin from soil strfaces.

(c) Microbial degradation of endrin occurs anaerobically and isaccelerated by conditions such as flooding and soil deprh.

33

4.'t.4

Environmental transport, Qistribution, and transformation

(d) Soil cultivation and crop rotation accelerate the dissipation ofendrin.

(e) When the percentage of organic matter is high, as in muck -soils, the persistence of eldrin is greater. In sandy soils,volatilization is high and persistence is low.

Soil-plants

River and basin sediment was brought on land near Rotterdam, theNetherlands, after dredging. Once the sediment had settled for severalyears, the land was used for agriculture, Some of the sediment came froma basin near a pesticide manufacturing plant and was contaminated withmany organochlorine hydrocarbons, including the pesticideshexachlorobenzene, aldrin, dieldrin, and endrin. The mean concentrationof endrin in the sediment of the basin near the plant (expressed in mg/kgon a dry weight basis) was 0.48 (range, 0.01-2.6) n 1976 and 0.59(< 0.01-3.6) in 1977. In crops, the concentration of endrin ranged fromnone detected to 0.06 mglkg of product; in carrots, however, levels up to0.73 mg/kg were found (Wegman et al., 1981).

Abiotic degradation

When endrin was heated to above 200 "C, as can occur during gas-liquid chromatography ar 230 oC, the molecule was isomerized to aketone, delta-ketoendrin (1, Fig. l) and an aldehyde (3). A minor productoI the thermal reirrangement was an isomeric alcohol (4). Endrin is alsotransformed to delta-ketoendrin (1) under acid-catalysed conditions(Phillips et al., 1962).

kradiation with ultraviolet light for 48 h alsoresults in rearrangementto this ketone (37Vo) and, to a much lesser extent, to the aldehyde (97o)(Rosen et al., 1966; Plimmer, 1972; Mukerjee, 1985). Endrinunderwenta photolytic reaction in hexane and in cyclohexane after irradiation at253.7 and300 nm,resulting inahalf-cageketone,pentachlorophotoproduct(2), in80Vo yield. This photolytic product has also been identified in thefield and was found to be highly resistant to oxidation and reduction(Plimmer, 19721'Zabik et al., 1971; Mukerjee, 1985). When an acetonesolution of endrin was irradiated with light from a mercury lamp in a quartzcell for 2Ah, rluee metabolites were formed by the loss of one chlorineatom from the initially produced delta-ketoendrin; one of these wascompound 2 (Dureja et al., 1987).

34

4.2

EHC 130: Endrln

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35

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Environmenta I tra n sport, d istrlbution, and transformation

4.3

Endrin has been reported to isomerize to delta-ketoendrin during5 years' storage in the dark at room temperature (Plimmer, 1972.

kr sunlight, mainly the ketone is formed (Soto & Deichmarur" 1967;Roser; 1972); approximately 5Mo isomerization to the ketone took placewithinT t 2 days with exposure to intense sunmer srm (Burton & Pollard,r974).

Thephotochemicalproducts are imponant as terminalresidues: delta-ketoendrin was found on cotton plants and on cabbage and apple leavesafter application of endrin (Plimrner, 1971: Mukerjee, 1985).

Biotransformation

The mechanisms by which endrin is removed from the environmentinclude photodecomposition and bacterial degradation. These factors andtheii effects on the persistence of endrin have been reviewed by the USEnvironmental Protection Agency (Donoso et al., 1979).

4.5.1 Biodegradation

Microbial degradation of endrin depends on the presence of anappropriate microbial species and suitable soil conditions; it occurs underanaerobic conditions (Donoso et at., 1979). Biodegradation is aided byfungi and bacteria such as Tric hode rma, P seudomonas, arrd Bacillus. Themajor ffansformation product is delra-ketoendrin (Patil et al., 1970).

About 150 isolates from various soil samples were screened toinvestigate the role of these microorganisms in degrading endrin; 25 of the150 isolates were active. At least seven metabolites were fowrd, butconversion of endrin into the ketoendrin was common throughout(Matsumura et al., 1971).

4.3.2 Bioaccumulationandbiomagnitication

The bioconcentration factors cited below are simple rarios of theexposure concentration and the concentration in organic tissues. Theyshould be used with caution as indicators of bioaccumulation potential: ahigh bioconcentration factor can represent little uptake of a lowconcentration, and a low bioconcentration factor can be found withconsiderable uptake of a high concentration. The bioconcentration factor

36

EHC 130: Endrln

should therefore always be cited with thepertinent exposwe concentrationof endrin.

Soil invertebrates such as slugs and earthworms had bioconcentrationfactors of 14 to 103. Bioconcentrdtion factors in a number of aquaticorganisms are given in Table 4. These ratios differ extensively betweendifferent qpes of aquatic organisms. Bioconcentration factors of 140 to222 were found for four blue-green algae,(Microcystis aeruginosa,Anabaena cylindrica, Scenedesmus quadricauda, and an Oedogoniumspecies) after 7 days' exposure to endrin at a concentration of I mg/litre ofwater( Vance & Drummond, 1969). In a study of the accumulation ofendrin in stoneflies (Pteronarcys dorsata) exposed to 0.03, 0.07, and0.15 pgllitre of water, the bioconcentration factor ranged from ll30 to348, decreasing with increasing water concentrations over the 28-dayexposure period (Anderson & DeFoe, 1980). h bullheads (lctalurusrnelas), the bioconcentration factor was 3700 after exposure for 4 days to0.60 pgllitre and 6200 after exposure for 7 days to 0.26 pglitre (Anderson& DeFoe, 1980). The bioconcentration factors for endrin in sub-aduls ofleopard frogs (Rana splwnoce phala) exposed to 0.01, 0.012, O.016, 0.022,and 0.030 mg,/litre were 7 1.4, 3 4.4, 5 1.8, 59.4, and 9 4.3, respectively. Sub-adults exposed to 0.01, 0.012, and 0.016 mg/itre for 96 h and sacrificed60 h later had bioconcentration factors of 6.1, 4.8, md 1.2, respectively(Hall & Swineford, 1980), indicating a relatively rapid elimination ofresidues.

In daphnids and molluscs, a direct linear relationship was foundbetween the logarithm of the equilibrium bioconcentration factor (and thereciprocal clearance rate constant) and the log P octanol/water partitioncoefficient for non-degradable, lipophilic compounds with partitioncoefficients rangmg from 2 to 6. This relationship permits calculation ofthe times required for equilibrirm and for significant bioconcentration oflipophilic chemicals, which were found to be shorter for molluscs than fordaphnids. The equilibrium biotic concentration for both molluscs anddaphnids decreased with increasing chemical hydrophobicity. Therelationship between the bioconcentration factor and log P octanol/waterpartition coeffi cient was linear for compounds that didnot attain equilibriumwithin a finite exposure time (Hawker & Connell, 1986).

In a study of the bioaccumulation of endrin from food by lobsters(Homarus americanus), endrin dissolved in methanol was added tosea water, and mussel tissue was soaked in the solution for 2 h to provide

37

Environmental transport, distribution, and transformation

Table 4. Bioconcentration factors for endrin in aquatic species

Species Concentration Lenqh ol Bioconcen- Relerenceof endrin in expSsure tration tactorwater (pg/litre)

Clam(Mercenariamercenarial

Mussel(Hyridellaaus|/alis)

Eastern oyster(Crassostreavirginica)

Water flea(Daphniamagna)

Fatheadminnow(Pinephalespromelasl

Spot(Leiostomusxanthurus)

Flag fish(Jordanellatloridae)

Mosquitolawae (Culexipiensquinquetasc,btus)

Mosquito fish(Gambusiaaffinisl

Channel catfish(lctaluruspunctatus)

5 days 480

24days 38

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Lowe (1966)

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aconcentrationof endrinof 4.7 mgkgwet weight' Lobsters werefedtheprepared food every other day for 2 weeks, and excretion was followed for

an additional 4 weeks during which time the lobsters were fed

uncontaminated tissue. Liver and muscle were analysed from two or three

lobsters sampled after feedings L, 2, 3, 5, and 7, and from one or two

lobsters sampled during the excretion phase at 1,2, atf, 4 weeks. The

concentration of endrin reached a maximum of 1.95 mglkg wet weight in

the liver after 2 weeks of feeding; this level declined by abott 65Vo aftq

4 weeks of excretion. The time to 907o equilibrium (uptake) was 15 weeks,

and the time to SWo cleararrce (excretion) was 4 weeks (Mcleese et al',

r980).

Bluegill sunfish (Lepomis macrochirw) exposed to water containing1aC-labelled endrin at l pgllitre at temperatures of 2O-22 oC rapidly

absorbed the radioactivity, and, within48 h,914o of theradioactive endrin

had been taken up (6Vo was lost by volatilization from a control tank

without fish). Within 8 days after thefishhadbeen replaced inclean water,

less than 157o of the absorbed label had been eliminated; for three fish left

for a longer period, the half-life of loss was about 4 weeks, the loss curve

being linear (Sundershan & Khan, 1980)' Endrin accumulated rapidly in

the tissues of channel catfish (Ictalurus punctatus) exposed to nominal

concentrations of 0.(X, 0.4, or 4.A mgikg of diet for 198 days. After ttrat

time, all groups were fed an endrin-free diet. Endrin was not detected28 days later in fish that had received 0.(X or 0.4 mglkg, and the level in

the group that hadreceived4.0 mg/kg decreased to 0'011 mg/kg of tissuein 28 days and was below the limil of detection within4l days (Argyle etal., 1973). Similarresults wereobtainedforL eiostomas xantlnrus exporedto 0.05 pg/litre of water: at the end of the study at 5 months, a residue level

of 78 ltgkgtissue was found, and no endrin was detected in fish after 18days inuncontaminated water(lowe, 1965). Endrinthus seems todisappearrapidly from tissues. h2nTilapiazilli (Alexandria strain) fry (3'36 cm,825 mg) exposed to 0.025 pgAine (one+enth of the 96-h LCro) for 28 days,the total content of endrinwas327.4, 167.4,297.6,446.5, and595'4 ltglkg after 4, 7,14,21, and 28 days, respectively (El-Sebae, 1987)'

Sheepshead minnow (Cyprinodon variegatus) were exposed for23 weeks to endrin at levels of O.O274.72 pgllitre of water, from theembryonic stage through hatching until adulthood and spawning (see

section7.2.2.2). Four-week-old juvenile fish accumulated 25fi) times theconcentration in the water, adults, 6400 times, and their eggs,5700 times(Hansen et al., 1977).

39

Envlronmental transport, dlstrlbutlon, and transformation

The transfer of en&in through the food chain licherrreindeer-humans was studied in the northern part of Sweden by analysing lichen{Cladonia alpestris), a major food source for reindeer during the winter,together with samples of tissues from reindeer, which are eaten inconsiderable quantities by Lapps. One 4-year-old reindeer was slaughteredin 1979 and a 3-year-old in 1981, and muscle and liver were taken foranalysis. The armual uptake by reindeer was 2.0 mg. The average level ofendrin in lichen was l.9l (range, 1.27-2.78) ltgfug; t.+S a\d 2.41tghgwere found in the muscle samples from the two reindeer and 0.55 ard4.72 ltgkg in liver. The calculated transfer of endrin from lichen roreindeer was 0.77o. The estimated annual consumption of reindeer muscleby Lapps was 70 kg for males and 32 kg for womery consumption of liverwas 3 and 1.1 kg, respectively. The armual intake of endrin was thus30.3 pg for males and 13.8 pg for females (Villeneuve et a1.,1985).

40

5.1

5. ENVIRONMENTAL LEVELS AND HUMANEXPOSURE

Many of the data reported in this chapter are measurements taken at atime when endrin was used much more widely than at present or with littlecontrol orrestriction. They are therefore areflectionofahistorical situationin many corurtries. These data are included in the document as an indicationof the result of indiscriminate use and disposal of endrin. Data fromcountries where endrin may still be used are scarce or unavailable.

Environmental levels

The levels ofresidues associated with the use ofendrin in agricultureor with the discharge of industrial effl uents containing endrin are summarizedin Tables 5-9; the levels ofresidues less easily associated with specific usesor discharges are given in Table 10.

Air

A critical summary of studies on the atmospheric levels of pesticidesin the USA, e.g., in community air, was made by Donoso er al. (1979).Some of their conclusions are worth repeating: "Endrin concentrations arehighest in the atrnosphere over agricultural areas and probably reach theirpeak levels dwing thepesticideuse season. Of all urbancommunities thosesurrounded by farmlands run the highest chance of atmosphericcontamination. Urban communities far removed from agricultural areasare unlikely to experience significant contamination. " llhe maximum levelofendrinin air,58.5 ng/nf , was foundin arural townin an agricultural areain the south of the USA, but the normal weekly variation was between 0.8and 6.5 ng/m3 (Stanley et al., 1971). In a later study of the same rown, theaverage annual atmospheric levels were3.2nglm3in 19'12,2.3 ng/m3in197 3,and 5.3 ng/m3 in I 974, with the highest levels in August; in I 974, rhiswas 2'l .2nglm3 (Arthur et al., 1976). The resulrs of a national monitoringprogrammeforpesticides inthe airof various states of theUSA showed theoccasional presence of endrin over agricultural areas at levels of the sameorder of magnitude: mean of positive samples (8Eo),2.6nglmr, with amaximum value of 19.2 ng,/nf (Kutz et al., 1976).

Endrin was not found in rain-water collected at different location in theUnited Kingdom, using a method wirh a derection level of I nglirre of

5.1.1

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water(farant&Tatton, 1968), nor inatrnospheric air(Abbottetal., 1966);however, endrin has never been used extensively in the United Kingdom.

Themean daily intake of endrin by ffialation in thewestempart of theNetherlands was calculated on the basis of an air concentration of 4l pg/m3 (maximum, 300 pg/rrf) to be 0.S pglday or0.3 mgfear, on the basis ofair samples taken in the period 1975-81 (Guicherit & Schulting, 1985).

Table 7. Concentrations of endrin in organisms collected in a cotton-growingarea in the Republic of Chad in 1969

Sample No. of Concenfation (mS/kS) CommentssamPles

M"." R*s"

Fish, twospecies

Kingfishers andcormorants; liver

Birds, non-aquatic,various species

BrainLiver

1 21 2

0.02

0.02

0.510.88

LD-O.083

LD-O.075

0.1H.770.13-1 .42

Cottonjrowing area,endrin and DDT usedfor pest control; limitof detection, 0.008mg/kg

Birds found deadsoon after insecticideapplication; deathsof some birds atbibu-ted to endrin

From Everaarts et al. (1971); LD, limit of detection

5.1.2 Soll, sediments, and sewage sludge

5.1.2.1 Soil

In theUS National Soil Monitoring ProgranL 1486 soil samples from37 states were analysed :ur,l97l. Fourteen samples were found to containendrin, at a geometric mean level of < 0.001 (maximunr, 0.02-1.00) mg/kg dry weight (Carey et al., 1978). The mean endrin concentration in29 soil samples in Kyushu Disrricr, Japan,was 0. I 83 mg/kg (range, 0.0 I 6-0.629 mgTkg) dry mauer (Suzuki et al.,1973).

5.1.2.2 Sediments

In 1964, levels in rhe sedimenr of Cypress Creek, Memphis, TN, USA,upstrqlm and downstream of a pesticide manufacturing plant, reached12 80O mg/kg dry weight. In 1967 , warer from the Creek contained levels

50

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of 0.27 -2.03 pgfl itre and sediment contained levels of 4? .4-lO 67 6 mg/rgdry weight (Barthel et al., 1969).

Endrin was found in l77o of samples of bottom sediment from 59 siteson the Detroit River, USA, at levels up to 43 ltgkg (limit of detection,1.0 pg&g) (Harndy & Post, 1985). No endrin was detected in sedimentsamples collected in 1980-82 from riverine and pothole wetlands at17 locations in the north--central USA (Martin & Hartman, 1985) or insamples of sediment from 34 stations on the upper Great Lakes in 1974(< I ttglkd (Glooschenko et al., 1976).

None of 60 samples of bottom deposit collected in 1974 from 19 riversand their estuaries in Japan contained endrin (< 0.01 mg/kg) (JapaneseEnvironmental Agency, 1975).

No endrin was detected in sediment and particulates from the RiverElbe in Germany in I 983-85 (S turm et al., I 986). Sediment from RotterdarnHarbour contained a total of 3-59 Fglkg aldrin, dieldrin, and endrin. Noendrin was found at seven sites in the Elbe Estuary (Japenga et al', 1987)'A housing estate in the Netherlands, comprising about 800 houses andpublic buildings, was built in 1983 directly on a 4-m+hick layer of harboursludge transfened in 1962-64 from about 20 harbour basins in Rotterdamand the industrial area around the Nieuwe Waterweg. Organic solvents,polycyclic aromatic hydrocarbons, heavy metals, and endrin and relatedpesticides, were detected in the sludge. One-third of the soil samplescollectedin the gardens (7 I locations), 0-40 cmbelow thesurface, containedendrin and related pesticides at a mean concentration of 1.2 mg4dg and amaximal concentration of 19.5 mgftg dry weight (Van Wynen & Stijkel,1988).

In surface sediments from'five sites in Manukan Harbour. NewZealand, only traces (none detected to < 0.1 pg/kg dry weight) of endrinwere found fox et al., 1988).

Particulates from two sites in the Shatt al Arab River in Iraq containedendrin at 84 and 154 pglkg, and a site in the Tigris River containedZl7 ltglkg. No endrin was found in the Euphrates River. The mean concentrationof endrin in surface and subsurface sediment from the Shatt al Arab Riverranged from 3 to 18 (range, none detected to 32) pgfkg; no endrin wasfound in surface and subsurface sediment from the Tigris River. None wasfound in surface sediment from the Euphrates River, but in subsurface

67

Environmental levels and human exposurc

sediment a mean concentration of 1 1 (5-25) pgTkg was detected @ouAbulet al., 1988).

5.1.2.3 Sewage sludge

Endrin was found in only a few of 444 sludge samples analysed fromsewage fteatrnent works in the united Kingdom. The mean concentrationwas 0. 1 I mg/kg of sludge, with a range of 0.0l-O.7 I mg/kg (Irdclntyre &Lester, 1984). All samples of non-disinfected influent at a pilot plant inJefferson Parish, LA, USA, contained endrin, at an average concentrationof 0.67 (0.25-l.58) ngline (Lykins et al., 1986).

Sludge from three main waste water treatment plants in Kuwait wasanalysed over a 6-month period in 1984-85. Two grab samples were takenfromeachplant every month togivea total of 36 samples. Themean endrinlevels for the three plants were 0.A2, 0.02, and 0.06 mg/kg (Samhan &Ghobrial, 1987). Sewage plant effluents before and after treatment wereanalysed in Baghdad (haq) in 1982-83. Endrin was found in 8/15 samplestakenbefore treatrnent, at amean concentrationof0.2g I (0.08l-2.637) ltgllitre, and in 6/15 samples taken after treatment, at a mean concentration of0.194 (0.072-1.197) pgllitre (Al-Omar et al., 1985a).

5.1.3 Water

5.1.3.1 Surtace water

Data on the concentrations of endrin in surface water concem mainlythose regions in the USA where use of endrin was widespread, such as inMississippi and Missouri, over the period 1957-65. The highestconcentrations were found in 1963 in the Lower Mississippi, with amaximum level of 0.214 ltglitre. The concentrations and the rate ofoccurrence decreased considerably later (Breidenbach et al., 1967),ln asurvey in 19&48, a maximal level of 0. I 33 pg/litre was reporred ro havebeen found in the Missouri basin in 1967. No endrin was detected in 1968(Lichtenberg et al., 1970). In 1974, the concenrrations in the LowerMississippi was 0.0045 pgllitre in Augusr-November (Brodtmann, 19?6).

In one sample from the Potomac River, at Quantico, endrin and endrinaldehyde were identified at concentrarions of 0.fi)5 urd 0.006 pgllitre,respectively (Hall et al., I 987). Endrin was not found in the w aters near theL,os Angeles County ocean ourfalls (< 0.00005 Fgllitrey (Green et al.,

68

EI]C 130: Endrin

1986) or in surface water in Louisiana in 1980 (< 1.0 ng/litre) (McFall etal., 1985). In a programme to monitor surface water in the USA in 1976-80, endrin was found in only O.lVo of samples, at a rnaximum value of0.(X pglitre (Carey & Kutz, 1985).

No endrin was found in water from 33 sites in the Upper Great Lakesin Canada (< 0.01 pg/litre) (Glooschenko et al., 1976)' In Ontario, whereendrin was used only sparingly, no residues were found in 197 I or I 975-77 (Miles & Harris, 1973; Frank et al., 1981). In water samples taken I mbelow the surface at 14 stations onLakeOntario in 19811, endrin was foundin concentrations of 0.000044-0.m0145 pg/itre (Biberhofer & Stevens,1987).

In a survey of the aquatic environment in The Netherlands, includingdrinking-water, 1826 samples were taken at 99 sampling sites betweenSeptember 1969 and 1977; traces of endrin were reported occasionally(Wegman & Greve, 1978, 1980). Studies of surface water in other areas inEurope failed to show the presence of endrin (Wilson Committee, 1969;Engst & Knoll, 1 973; Uhnak et al., 197 4; Galassi & Provini, I 98 I ;Hrubec,1988). In 1984-85, water from a number of rivers in Germany containedendrin at levels ofnone detected to0.30 Pglitre (Braun,1985); surfacewater in Greece occasionally contained levels of 0.0003-0.0004 pgllitre(Albanis et al., 1986).

No cndrin was found in surface or drinking-water in the state of Sa6Paulo (Brazil) (Lara & Bancto, 1972), but it was found in water reseryoirsof basins in Sad Paulo at concentrations of none detected to 1.02 Fglitre(Celcstc & Caccrcs, 1987; Cacercs et al., 1987). En<irin was also foundaccidcntally in two lagoons in north-west Mexico (Rosales et al., 1985).

None of 60 water samples collected in 1974 from 19 rivers and theirestuaries inJapancontainedendrin (< 0. 1 pflitre) (JapaneseEnvironmentalAgency, 1975).

Endrin was found at five places in the River Nile at concentrations of0.0038--0.0189 pgllitrc in March-September 1982 (El-Dib & Badawy,1 985). In analyscs of the watcr of thc Shatt al Arab, Euphrates, and TigrisRivers, cndrin was found only in the Euphrates River, but in all samplesat a mcan conccntration of 0.024 (0.014-0.036) pg/litre (DouAbul et al.,1988). It occurrc,Jin'l5o/o of samplcs of urban, industrial, and continentalwatcr from thc Moroccan Mcditcrrancan coast. at concentrations of none

69


detected to 13 pgllirre (Kassabi et al., 1988). Three of 15 grab samples ofsurface water sources in Southem Africa (Orange Free State) containedendrin, at a concentration of 2-4 Fgllitre (Hassett er al., 1987).

Endrin was present in the Kalinadi River in India as a result of runoff,especiallyfrom agricultural areas, ar aconcentrationof 2 pg/itre (Kudesia& Bali, 1985). kr the ChaoPhraya River andklongs in Bangkok, Thailand,no endrin (< 0.001 pgnife) was found in 19M (Onodera & Tabucanon,1986). Analyses in Bali of 16 samples of river water in the dry season and15 samples in therainy season showed thepresenceof endrin at 40 pgnitreonce, in the rainy season (Machbub et al., 1988).

5.1.3.2 Rain and snow

No endrin was found (limit of detection, 1-2 ng/itre) in atmosphericprecipitation in rhe form of snow ( I 7 samples in I 976) and rain (8 I samplesin 1976 and 1977) on the Canadian side of rhe Grear Lakes and inland inareas remote from any nearby industrial or urban contamination (strachanet al., 1980). Four of 16 samples of rain-warer collected ar four sites inCanada had levels of 0.00013-O.09044 Fgllire and anorher sample had0.0048 pgllitre; no endrin was detecred in the orher 1 1 samples. The meanendrin contents in samples taken ar anorher site in 1977, 1981, 1983, and1984 were none derecred, 0.000ffi5, 0.000085, and 0.0fi)049 Fgflitre,respectively (Strachan, 1988). Endrin was nor detecred in snow samplescollected ar 12 sires in the Northwest Territories of canada in 19g5-g6(Gregor & Gummer, 1989).

5.1.3.3 Drinking-water

Data obtained in 19&-67 from selected municipal drinking-watertreatment plants in Mississippi and Missouri, USA, showed thar theconcentration in approximately lU%o of the samples exceeded 0. I pgllitrein the first year but that the concentrarions were lower in 196547 (Schaferet al., 1969). The most recenr srudy on US drinking-water was done onfinished waterin New Orleans, LA, in 1974, where thehighest concenrrationmeasured was 4 ng/litre (US EPA, 1974).

During 1976, endrin was found at a mean concenrrarion of 4 ngflitre(range, l-7 ngllitre) in drinking-water in Ouawa, Canada (Williams er al.,1978).

70

EHC 130: Endrtn

The mean concentration of endrin in drinking-water at the El-Abbasiastation, Egypt, in 1986 was 3.507 t 1.45 ng/itre in 10 samples taken

before purification and 1.845 + 1.29 nglliue after purification (Abdel-

Razik et al. 1988).

Drinking-water from the North Coast region of New South Wales,

Australia, was analysed in 1986-87: 147 of 659 samples contained tracesof endrin (none detected [< 0.005] to 0.05 FeAitrel (Ang et al., 1989)'

i.l.3.4 Groundwater

Water in wells used as a source of water for mixing pesticides in fruit

orchards inWestVirginia (USA) was found tocontain endrin at about I ng/

litre in 1985 and in 1986. The water in these wells was not used fordrinking-water. Endrin had not been used in the area since 1970, and theauthors cite their results as evidence for the persistence of endrin and its

capacity to conJaminate groundwater many years after cessation of use(Hogmire et al., 1990).

i.l.4 Organisms in the environment

;.1.4.1 Birds

Endrin was found in the carcasses of four of 16 turkey vultures(Cathartes aura) in southern Califomia, USA, in 1981, at levels of 0.11-0.23 mglkg wet weight, but in none of six common ravens (Corvus corax).It was also found in two offour vulture eggs, at 0.10 (range, none detecledto 0.52) mg/kg wet weight, but innone of 30 raven eggs (Wiemeyer et al.,1986).

Endrin was found in eggs of shag (Phalacrocorax aristotelis) andconnorants (Phalacrocorax carbo) at one of five collection sites in theeast, south-east, and south of keland, at a geometric mean concentration of0.30 (range, 0.06-1.60) Fg/kg (Wilson & Earley, 1986). Eggs from twospecies ofpasserine birds, three species ofgull, four species oftem, and thenight heron were collected in Italy in 1 982-83. Endrin w as found in 30 eggsofthe night heron (Nicticorax nycticorax), at an average concentration of0.I 1 (0.03--0.27) mg/kg, in 50 eggs of the gull-billed tem (Geloclelidonnilotica), at a concentration of 0.28 (0.05-1.31) mgkg, and in 38 eggs ofthe tree sparrow (Passer montanus) and 33 eggs of the hooded crow(Corvus corone), at concentrations of 0.17 (0.09-0.33) and 0'21 (0.07-

71


0.31) mg/kg. It was not derected in eggs of the other species (Fasola er al.,1987).

No endrin was found in 98 eggs or in the Iivers of 112 nestlings ofrooks (C o nus frugilegrz,s) collected fromfi ve rookeries in northem Germanyin 1982-83 (Beyerbach et al., 1987) or in 45 eggs and the livers ofeightyoung lapwings (Vane llus vanellus) collected in I 984 and I 986(Beyerbacher al., 1988).

Detectable residues of the comrnonest organochl'rine pcsticides wcrefound in 0.9Vo of l12pools (mostly of l0birds) of srarlings (Sturnusvulgaris) collected in l29sites in the USA in 1979 and in 1.6Vo of129 pools in 19{J2. In mosr srares, no endrin was derectec.l, but levels of 0.01and 0.17 mg/kg wet weight were found in two (Bunck et al., l9g7).

Endrin was present at microgram levels per kilogram of wet weighr in272 samples of liver, muscle, fat, and eggs fromnorrhem fulmars (F ulmarusg lacialis), black-legged kiuiwakes (R is sa tr idac ty la), and thick-bi lledmurres (Uria lomvia) collecred in 1975-77 on prince Leopolcl Island,Northwest Territories, Canada (Netrleship & peakall, l9S7). Ir was foundin 8 of 108 carcasses of herons analysed in the USA since I 966, ar levelsof 0.10-O.86 mg/kg wet weighr (Ohlendorf et al., 1981) but was nor foundin 255 pools of wings from black ducks (Ancs rubripes) and mallards (.21.plaryrhynchos) collected in the USA in l98l-82 (proury & Bunck, l9g6).

Endrin was not derected in six eggs of Forster's Lem (Slernafc,rsteri)collected on Creen Bay and Lake poygan, Michigan, USA in l9g3(Kubiak et al., 1989). None was found in a toral of 107 eggs collected in1975-80 from l0 species of colonialvarerbirds nesring in areas aroundGreen Bay and Lake Michigan. The species were liule gulls (Laresmi nutes), grenn-backed heron s (B uto ride s striatus),black tems (C ht Mo niasniger),hening gulls (L. argentatus), ring-billed gulls (L. delawarensis),common tems (S. hirundo), Forster's tem (S. forsteri), double_crestedcormorants (P halcroc o rax aarllls), black-crowned ni ght h er ons (N y c t ico raxnycticorax), and cattle egrets (Bubulcu.l lbis). The limir of derecr.ion was0. 1 mg/kg in 1977 and 0.05 mg/kg in 1978 (Heinz et al., 1985).

Of five eggs from peregrine falcons (Falco peregrlnas) collected inArizona, USA, in 1978-82, one collecred in l97ti contained endrin ar0.20mg/kg dry weighr, one collected in l98l contained no derecrableamount (< 0.01 mg/kg) and rhree collected in l9g2 contained 0.02_0.&t mg/kg (Eltis et al., 1989).

72

EHC 130: Endrin

No endrin was detected 'n

T7 eggs from tree sparows (Passer

montanus),4 eggs from house martins (Delichon urbica),28 eggs fromwhite storks (Ciconia ciconia), or eggs from nine other species of bird inGermany in 1984. The livers of 25 nestling, 13 young, and 17 adult white

storks also contained no detectable level of this pesticide (limit of detection,0.001 mg/kg) (Heidmann et al., 1989).

1.4.2 Fish and shellfish

The endrin concentrations in red mullet (M ullet barbatus) collected atsix locations in the Pagassitikos Gulf (Greece) in 1985-87 were < 0'005-0.5 pglkg fresh weight of fillets (Satsmadjis et al., 1988)' The meanconcentrations inliver, brain, kidneys, andmuscleof 22 ttout(Salmo trutta

farioL.) taken from four rivers in Ledn, Spain, in 1985 were 0. 1(X, 0' 123,0.157, and 0.1 57 ngftlgwet weight. The incidence in the four organs was4.54-22.73Vo (Teran & Siena, 1987). Endrin was found in 29 samples offi sh collected in Italy, at a median concentration of 0'0 19 mglkg (Cantoni

et al., 1988). Organochlorine compounds were measured in three samplesof liver from c od (Gadus morhua) colle*telin three areas of the North Seain 1977 -37 ; endrin was present at a concentration of < 5 pg/kg of product(De Boer, 1989).

Endrin was not detected (< 0.01 mg/kg) in two or three replicatesamples, each comprising three to five bluegill (Lepomis macrochirus) andcommon carp ( Cy p rinus carplo), collected from downstream sites exposedto irrigated agriculture and from non-i:rigated upstream sites on the SanJoaquin River and tributaries in Califomia, USA (Saiki & Schmitt, 1986).Endrin was also not found in waternear Los Angeles County oceanoutfalls(< 0.0m05 pcnire) or in mussels (Mytihu californianus) (< 0'1 ttg/kgwet weight) that had been suspended at the monitoring site for 2 months toprovide a measure of the bioaccumulation of chlorinated hydrocarboncontaminants (Green et al., 1986). No endrin was detected in fish samplestaken at nine locations in north--central USA (Martin & Hartman, 1985),and endrin was not detectable (< 0.00 I mg/kg) in 5 27 samples of edible fi nfishharvestedfrom ChesapeakeBay and its tributaries (Maryland) over theperiod 1976-80 or in 20 samples of roe and gonadal tissue @isenberg &Topping, 1985).

No detectable quantity (< I pg/kg) of endrin was found in two speciesof crayfish (Procambarus clarkii and P. acutus) commercially harvested

73


from dual-cropped ponds and from warers of the ̂ A,tchafalaya River Basinand the Mississippi River in southem Louisiana, or in sediment and watercollected from several ponds and at the Basin three times during 1986 and1987 (Madden er al., 1989).

Endrin was measured at levels of 0.4 and 66 ltgkgin American ecls(Anguilla rostrala) sampled at various sites between Lakc Ontario and themouth of the S[ Lawrence river in 1982 (Castonguay et al., l9g9). Endrinwas not detectable (< 0.002 mg/kg) in 'mosr' composite samples ( l _ I 5fish of l0 different species) collecred from 10 sites on the Crear Lakes andtributaries between I 980 and 1 98 I , although in a few cases concenrrationsup to 0.01 mg/kg were found (Devaulr, 1985). Endrin was nor present(< 0.005 mg/kg) in fillets of Fall Run Coho salmon (Oncorhynchuskisutch) taken from 14 sires on the Grear Lakes in 1984. In mosr cases,three samples per site were analysed, and the fish were 2-3 years old(Devault et al., 1988). Johnson er al. (1988) measured rhe inpur oforganochlorine pesticides from precipitation and runoff to five small lakesperipheral [o the canadian Great Lakes and the levcls of rcsiducs in fishcaught in the lakes. While cndrin was dctectable in precipitation (at 0.46and 0.54 nglitrc at the lwo sampling sitcs), nonc was measurcd in runoffwatcr and no dctectablc residue was fbund in fish.

Thc mcan conccntrarions of endrin in I 3 commcrcial ly important fishspecies collcctc'd in thc north-west Arabian Gulf varicd bctween I and28 ftgkg, and thoso in fivc spocies collecred from Hor al-Hammar Lake inIraq in 1985 were347 pg/kg wer weight of edible rissue. Enclrin rcsiducswcre dctccrcd in approximar ely 9oo/o of the fish (DouAbul ct al., l9g?a).Sampfcs of Barbus xanlhopetrus collected in thc Shatt al Arab River anclin Hor al Hammar Lake containc<l avcragc conccntrations ol'4 (noncdctected to 9) and 20 ( I 1-27) lt glkg,while Indian shccJ (l'enuaktsa ilistra)from thc Shau al Arab Rivor conrained {i0 (57- | 0l]) p8/kg (wcr woighr).Shrimp (Metapanaeus all'inis) did nor conrain cndrin (DouAbul cr al.,1987b). fn l9ti4, B. xanthopetru.r. Iiom rhc Rivcr conraincd a meanconccntration of 16 pg/kg wer weight, and thosc frorn rhc Lake, 154 pg/kg (range, l3-355); Indian shcd had mcan conccnrrarions<tf 4l_147 1tg/kg (range, nonc dcrccrcd t<> 236) (DouAbul cr al., 1987c). Freshwarermussel (Cbrb iculafluminea) collccted in the Shatr al Arab River conraincd166-540Fg/kg (rangc, t40-583) (DouAbul et al., 1988). Endrin wasprcsent at conccntrarions of 1.9-12.2 Fglkg of muscle rissue (wer weight)in three fish spccies and at 0.t18-7.7 ttskg in three T'ilapia speciescollectcd ncar Alcxandria, Egypr, in 1985 (El Nabawi cr al., 19g7).

74

EHC 130: Endrin

Endrin was present at 0.003-O.004 mglkg in black pomfret(P aras t ro mateus niger), mackerel (Rastrellig e r kanagurta), and marinevala (Chirocenlrzs sp.) and at 0.08 mglkg in Ex:n (Euthynnus affinis)collected off the Indian coast (Radhalaishnan & Antony, 1989)' It wasfound in one sample of fish at 0.019 mg/kg wet weiSht and in one shellfishsample at 0.034 mglkg but in none of 312 other specimers of I I types offish, crustaceans, and molluscs obtained from five sites in Java, Indonesia(limit of detection, 0.01 mglkg) (Koeman et al., 1974).

No endrin was forurd (< 0.005 mg/kg) in 60 samples of fish andshellfish collected in l9 rivers and theirestuaries inJapan in 1974 (JapaneseEnvironmental Agency, 1975).

The median concentration of endrin in the eggs of 15 adult chinooksalmon(O ncho rhy nc hus ts hawyts cha) collected in Lake Michigan in I 982was 23.5 pg/kg wet weight (range, 3.9-126.3) (Giesy et al', 1986)'

Composite samples of wholefishof selected species were collected in1983 near the shores of 13 tributaries of Lake Michigan and GrandTraverse Bay. Two of each of the following species were collected fromeach site: conrmon carp (Cyprinus carpio),bowfin(Amia calva), channelcatfish (lclalu rus punctatus), pumpkirseed (Lepomis gibbosas), rock bass(Amb loplite s rupesfrls), small-mouth bass (M ic ropte rus do lo mie u),lat ge-mouth bass (M. salnnides), lake trout (Salvelinus namoycush), and pike(Esor lacias); the composites comprised 3-1 1 fi sh. Endrin was not detected(limit, 0.fi)5 mg/kg) (Camanzo et al., 1987).

Yellow perch (P ercaflavencens) were sampled ineightreservoirs andlakes in Ohio and Wisconsin, USA, in 1978J9 ' Endrin was found in fourfish at levels of 0.008-0.02 mg/kg, which were much lower than the levelsfound of polychlorinated biphenyls, DDT and dieldrin (Carline & Lawal,1985).

1.4.3 Mixedspecies

Herons (Nyctanassa violacea), water snakes (Natrix spp.)n raccoons(P rocyon lotor), charnel catfish (Ictalurus punctatus),crappies (P otnoxisspp.), frogs (R ana spp.), and crawfish(P rocambarus clarkil) were collectedfrom three watersheds in Louisiana, USA in 1978-79- Endrin was foundin a heron at 0.014 mg/kg and in a catfish at0'022 mgAg, but inno othercase (limit of detection, < 0.05 me/kg) (Dowd et al., 1985)'

75


5.1.5 Other food and feed

5.1.5.1 Cereals

Endrin has been used extensively for the control of insect pests in rice.Typically, one to four applicatiorn aremade, depending on local conditions,the last application usually not later than one month before harvest. Dataon residue levels are available from India ( I 969-70), Thailand ( I 968-70),the Philippines, Indonesia (1965), and Venezuela (1969). The levels inpolished rice were 0.01--0.04 mg/kg of product (mean, 0.014 mgfkg),except in India where higher levels in the order of 0.12 mg/kg were found.Bran, which is used mainly :rs a component of poultry feed, contained amean level of 0.35 mglkg (range, < 0.01-2.3 mg&g), and low levels ofdelta-ketoendrin were found (FAOAMHO, 1971)

Endrin has been used to only a limited extent on grain crops. Theresidues in different tlpes of treated grains in the USA were generallybelow 0.05 mgtkg of producr, excepr in oars in which levels up to 0.5 mglkg were found. Ln India, up to five applications on sorghum gave residuelevels below 0.02 mg/kg; in the USA, the levels in sorghum were below0.05 mg/kg. Straw of cereals contains higher levels: rice straw had up to3 mg/kg,, and sorghum straw up to 0.4 mg/kg (FAOIilHO, l9Z1).

Wheat imported into the United Kingdom in 1987-88 did nor containendrin (< 0.01 me/kg) (Osbome et al., 1989).

5.1.5.2 Fruit and vegetables

Endrin is occasionally used for control of field mice (voles). Noresidue was found in apples at harvest (derecrion limir, 0.01--0.002 mglkgof whole fruit) when it was sprayed on the ground under trees in orchardsin autumn or spring. The levels were sometimes higher in fallen fruit,ranging from< 0.fi)2to0.02 mg/kg of product(Horsfall et al., 1970; FAO/wHo,1971).

Only 14 of 15 fiX) samples of fruit and vegetables imported intoSweden during the period 1981-84 contained endrin, at a maximumconcentration of O.02mgkg (Anderson, 1986). The pesricide analysisprogramme of the Swedish National Food Administration on fruit andvegetables, including potatoes, showedno residue of endrin above the 1imit

76

EHC 130: Endrin

of detection of O.O2 mgft;g in 13 724 samples analysed in 1985-87 (B.G.Ericsson, personal communication, 1990). The mean endrin concentrationin 137 samples of grape products (including seeds, skins, marc and lees) inItaly was 6.2-16.2 pglkg (Marinelli et al., 1986). Seven of 306 samples ofapples (fivetypes) collectedin 1980-83 fromfiveregions of Italy containedendrin (limit of detection,0.00l mg/kg) (Foschi et al., 1985).

InPakistan, in 16 samples of cucumbersprayed at the time of maturitywith a 0.057o endrin solution at a rate of 100 gallons/acte (1123 litres/ha),the endrin concentrations ranged from 3.(X to 6.69 mg&g. The residuespersisted in the edible portion of cucumber up to 14 days and diminishedthereafter (Illahi et al., 1986). Endrin was found in l77o of samples of peascollected from fields and markets in Faisalabad, Pakistan, at a level of L3-4.3zttglkg. The residues persisted for up to 12 days and then decreased(Illahi et al., 1987). No endrin was found(< 0.02 mg/kg) in 141 samples offruit and vegetables from Pakistan in 1982-83 (Masud & Farhat, 1985).

In an analysis of soya bean and soya bean straw in a US monitoringprograrnme, seven of 177 samples of soya beans contained a geometricalmean of < 0.001 (maximum, 0.03) mg/kg, and one of eight suaw samplescontained < 0.01 mgAg (Carey et al., 1978). Endrin was used in up to fourapplications on sugar-cane in the USA, with an interval of 45 days orlongerbetween the last application and harvest. Theresiduesfound incanewere usually < 0.05 mglkg of product (FAOAMHO, l97l).

i.l.5.3 Meat, poultry, and chicken eggs

Bovine fat (40 samples), pig fat (45 samples), calf fat (45 samples),sheep fat (22 samples), poultry fat (42 samples), and eggs (44 samples)analysed in the Netherlands in 1983 had a median endrin concentration of< 0.04 mg/kg (DutchAgricultural Advisory CommissiononEnvironmentalPollutants, 1983). No endrin was fowrd (detection limit,0.005 mg/kg) insamples of beef, pork, goat, mutton, poulory, or eggs analaysed in Italy in1985-87 (Cantoni et al., 1988) or in 'most' samples of pork, rabbit, orpoultry analysed in Rheinland/Pfalz, Germany, in l98l-84 (Kampe,1985). Dietary surveys in the United Kingdom demonsrrated no endrin inmeat (detection limit, 0.02 mg/kg) (United Kingdom Ministry ofAgriculture, Fisheries and Food, 1989).

Endrin was present in l0.8Vo of 2032 samples of bovine fat fromcarcasses collected from slaughterhouses in Brazil, at a mean level of

77

5.1.5.4


0.01 mglkg; the highest level was 0.09 mglkg of ri.ssue (De Paula Carvalhoet al., 1984). Endrin was presenr in hens' cggs lrom four of five areas inMexico, at concentrations of 0.00€. I I mg/kg of whole egg, and in I I of16 samples of chicken meat, at an average concentration of 0. l2 (nonedetected to 0.6) mg/kg on a far basis (Albert, 1990).

Endrin was detected in 86 of 221 samples of hens' eggs (78 narive and143 commercial) collecred in1975-:77 in Iran, ar a mean concenrration of0.017 (range, 0.003-{. 13) mg/kg (Hashemy-Tonkabony & Mossrofian,1979). No endrin was found (limit of detection, 0.02 mg/kg) in samples ofabout 25 eggs of scwc& ducks collected on 1l lcral markets in Java,lndonesia, in 1972 (Koeman et al.,1914).

It was found in 14of 367 hens'eggs collerctcd {rom 6l farms inI I districts of Kenya in 1984; in rhree of rhe eggs, rhc leve I was > O.Z mg/kg (Mugambi et al., 1989).

Heating, baking, frying, and steaming of tissues obrained frombroilers fed endrin at l0 mgkg of diet for 8 weeks did not significantlyreduce the level of residues: raw, 28.2; baked, 20.8; friet,22.1; andsteamed, 19.4 mgkg of dry rissue (Ritchey et a1.,1972).

Milk and milk products

The mean endrin concentrarion in 20 samples of fresh buffalo milk inKalubia, Egypt, was 0.02 mg/kg of milk far (range, < 0.01--0.03 mg/kg(Abdou et al., 1983). Cows' milk (39 samples) collecred in lirur areas ofBagdad, Iraq, in 1981-82 contained a mean of 60 (none detected to40O) 1tg/litre (Al-Omar et al., 1985b).

The average concenrration of endrin in l0 samples of evaporarcdcows' milk from three main cities in the agriculrural region of Mexico was< 0.007 mgllitre of milk far (Albert et a1.,1982). Endrin was found inpowdered milk at an average concentration of 0,06 mglkg and in checsc ata concentration of 10-27.2 mg/kg on a fat basis (Atbert, 1990).

The level of endrin in milk in rhe USA was < 0.001 mg/itre (on a fatbasis) (FAO/IVHO, 1971). No endrin (<0.5pg/lirre) was found in308 samples from bulk rransporrs of milk collecred in Ontario, Canada, in1977 (Frank et al., 1979) or in 359 samples collectcd in I 983 (Frank et al.,1985).

78

EHC 130: Endrtn

No residue was found (detection limit, < 0.005 mg/kg) in samples ofmilk, cream, butter, and cheese in Italy (Cantoni et al., 1988) or in12 samples of cows' milk collected in 1984-86 from different areas ofSpain (< 0.01 mg/kg fat) (Barcelo & Puignou, 1987).

i.l.5.5 Fat and oils

The most important use of endrin is for the control of insects in cotton,the number of applications being l-12; cottonseed oil is used for cookingand for the manufacture of margarine, while the extracted cake is used ascattle feed. Endrin is thus present both in the cottonseed and in the edibleoil and cakes. In a study ofthe extraction processes, it was found that alkaliwashing and bleaching had no marked effect but that deodorizationreduced the endrin levels to below the limit of detection (0.03 mgfkg)(Smith et al., 1968).

In field studies carried out in the USA, couonseed contained endrin ata maximum of 0.1 mg/kg, although the levels were usually much lower,delta-Ketoendrin was not detected. The levels in crude, decolourized, anddeodorized oil in Venezuela and Brazil were all < 0.02 mg/kg of product.Spot samples of refined cottonseed oil from California, USA, contained< 0.03 mg of endrin and < 0.02 mg of delta-ketoendrin ( limits of detection)

GAO^VHO,1971).

One-hundred-and-ten samples ofraw oil and ofoil at various stagesof proccssing, i.e., neutral i zed, hydrogenated, decolouri zed, deodorized,and shortcnings, wcrc collected from seven oil processing factories in kanin 1974. Endrin was found only in raw and neutralized vegetable oils, atconcenffations of 0.fiX--0.fi)5 mflitre. Raw imported and native oilscontaincd < 0. 0 I mgl i tre, cxcept for native sunflower oi I which contained0.026 mg/litrc (Hashcmy-Tonkabony & Soleimani-Amiri, 1 976).

Endrinwasfound in60 samples ofsix varieties of themajor edibleoilsand oil seeds used in India, including groundnut, sesame, mustard,coconut, and hydrogenatcd vcgctable oils, collected from a market inLucknow. Vegetable oil containcd 6 pgflitre, mustard oil, 72 ltgllitre, andscsame oil, 1690 1rg/kg. Of the different types of oil seeds, only mustardsced containcd cndrin, at22 ttgkg (Dikshith et al., 1989a).

Endrin was found at a mcan concentration of 0. 184 (0.097-O.288) mg/kg in samplcs of cod-liveroil analysed in Germany in 1985 (Ali, 1986). No

79


residue was found in vegetable oils and fats imported into the UnitedKingdom (detection limits,0.02 and 0.001 mg/kg, respectively) (Abbot etal., 1969).

5.1.5.6 Animal feed

. Residues ofendrin in pressed cottonseed cakes arise primarily fromthe l-5vo of oil left in the cake afrer extraction. The residues in cakes fromBrazil, lndia, the USA, and Venezuela were mainly < 0.01{).02 mg/kgproduct, levels up ro 0.08 mg/kg were found occasionally (FAOAVHO,l97l). The mean concentrarion of endrin in 32 samples of carrle feed froma local market in India was 0.020 mg/kg (range, 0.0134.027 mgAC)@ikshith et al., 1989b). No endrin was found in 79 samples of cattle feedin Pakistan (Parveen & Masud, 1987). Endrin was nor presenr in samplesof domestic and imported animal feed analysed in the USA in 1981-86(Luke et al., 1988).

None of 42 samples of chicken feed collected from 6l farms in11 districrs of Kenya in 1984 conrained endrin (Mugambi et al., 1989).

5.1.5 Miscellaneousproducts

Endrin was found in 5 of 25 robacco samples imported into Germanyat concentrations of 25-50 pglkg (Cetinkaya, 1988). No endrin was foundin cigarettes of 14 brands collected in Finland in 1960-84 (Mussalo-Rauhamaa et al., 1986). An average content of 0.006 pglcigarette (range,none detected to 0.O2 Stglcigarerre) was found in Switzerland (Zimmerli &Marek, 1973).

When raw cotton imported into Germany from 15 countries wasanalysed, endrin was found in samples from the USSR and Mexico at aconcentrarion of 3 pgTkg (Cetinkaya & Schenek, 1987).

5.2

5.2.1

Exposure of the general population

Total-diet studies

Studies on complete prepared meals in the USA, started in May 196 Iand continued to the present, have shown the occasional presence ofsmallamounts of endrin (Williams, 1964; Cummings, 1965, 1966; Duggan et al.,1966,196'71' Martin & Duggan, 1968; Comeliussen, 1969, 1970,1972:

80

EHC 130: Endrin

Manske & Comeliussen, 1974; Manske & Johrson, 1975; Johnson &

Manske, 1976, 1977; Manske & Johnson, 1977; Johnson et al', 1981a,

1984). These measurements indicate that the total average daily intake of

endrin from food decreased from 0'009 pglkg body weight in 1965 to

0.0005 pglkg body weight in 1970 (Duggan & Lipscomb, 1969; Duggan& Comeliussen, 1972),with a frrther decrease subsequently' In total-diet

studies of adults in the US A, representative foods were purchased in 27 UScities in 1980-82; the daily intake of endrin was found to be < 0'001 ttglkg body weight in 1978, but none was detected in 1979,1980, or 198 1-82(Gartrell et al., 1986a).

Further snrdies involvedretail purchase of 234 food items representativeof the total diet of eight US population grouPs in 1982-84 and preparingthem for consumption. The daily intake of endrin in the groups, which

included people aged 6-11 months, 2 years, 14-16 years (females)' 14-16 years (males), 25-30 years (females),25-30 years (males),6G65 years(females), and60-65 years (males), wasO.1-0'2 ng/kgbgdy weight (FDA,

1988; Gunderson, 1988).

Endrin was not present in the total dies of infants and toddlers in the

USAduring 1974-75 (Jolnsonetal., 1979). Itwas fowrdin one infantfoodsample at 0.011 mg/kg and in one sample of toddler food at 0.009 mg/kgof food in a study in 1975-:76 (Johnson et al', 1981b). Very low residuelevels were found occasionally in market-basket samples representing theaverage 2-week diets of infants (98 samples) and toddlers (110 samples)collected in l0cities in four geographic areas of the USA n 1917-:78(Podrebarac, 1984). In total-dietstudies of infants and toddlers in theUSA,representative foods were purchased in 13 US cities in 1980-82; the dailyintake of endrin by infants was found to be < 0.001 pg/i(g body weight in1978, and that by toddlers, < 0.001 pgAg body weight in 1979, but nonewas detected in the other years (Gartrell et al., 1986b).

Fresh food was bought from foru retail grocery stores in Toronto,Canada, in 1985 and combined in five food composites: fresh meat andeggs, root vegetables (including potatoes), fresh fruit, leafy and othersurface vegetables, and cows' milk. The concentrations of endrin in thefive composites were used to estimate the annual dietary intake of endrinfrom products in Ontario. Endrin was detected in all composites excepteggs and meat; the concentrations were 0.32 pg/kg in leafy vegetables,0.27 ltglkginfruit, 0.37 Fglkg in root vegetables, and0'27 pg/kg in milk.The total annual intake was estimated to be 3 1.8 pg,@erson (Davies, 1988).

8 1


In a total-diet study carried our in rhe United Kingdom in l9g5_gg,25 samples were obrained in 1984-85 which comprised the 16 foodgroups considered most likely to contain residues of organochlorinecompounds. No endrin was derected (limit of detecrion, 0.001--0.02 mg/kg, depending on the food group). Endrin w as also nor detected (< 0.0 I mg/kg) in 176 samples of pulses purchased from rerail our.lers in 19g6_g7.except in 3 of 2A samples of mung beans in which a mean value of< 0.01 mg/kg (range, none derected,to 0.06 mg^g) was found (UniredKingdom Ministry of Agriculture, Fisheries and Food, I 9g9). No endrinwas detected in complete prepared meals during surveys in the UnitedKingdom in 1965 (Robinson& McGilt, 1966; McGill & Robinson, 1968).Similar resulrs were obrained in Switzerland in 1973 (Zimmerli & Marek,1973), and very low levels were found in rwo of 73 samples analysed in1985 (wiithrich er al., 1985). No endrin residues werc found in roral-dicrstudies canied our in the Nerherlands in 1976-7g (Dc Vos cr al., l9g4).

5.2.2 Levels ln human tissues

Although the concentrations of many chlorinated hydrocarboninsecticides, such as DDT, dieldrin, hexachlorocyclohexanes, andhexachlorobenzene, and of their metabolites in blcxrd or adipose tissue o[the general population or ofoccupationaly exposed workers have beenfound to be an excellent index of the level of exposure of rhe gencralpopulation, this is not the case for endrin, becausc it is eliminated rapi<Jlv.

5.2.2.1 Adipose tissue

Except in a few cases, endrin was not demonstrated in adipose rissuesamples from the general population in the USA in 1962-66 (Hoffman etal., 1964, 1967), 1964 (Hayes er al., 1 965; Zavon eL al., I 965), lg7 0_7 4(Kutz et al.,l979a,b), and 1975-79 (US EpA, 1983); Canada in 1967_68(Kadis et al., 1970); Mexico in 1975 (Albert et al., 19g0); Argentina in1968-69; (Wassermann er al., 1969); Belgium in l963-69 (Wit, 1971); theUnited Kingdom in 196l (Hunter et al., 1963), 1964 (Robinson er al.,1965), and 196547 (Egan et al., 1965; Abbou er at., 1968, l9l-2); theNetherlands in 1969 (wit, l97l ); Switzrrlandinlgi2(zimmerli & Marek.1973); Germany in 1970 (Acker & Schulre, 1974); France in l97l(Foumier er al., 1972); Spain in 1978 (Henera Marteache et al., l97g);lndia in 1964 (Dale er al., 1965); or Wesrem Australia in 1965_66(Wassermann er al., 1968).

82

EHC 130: Endrtn

No endrin was found in 9l samples of adipose tissue obtained at

autopsy inKingston, Ontario, Canada, n1979 and 1981 or in 84'samples

from Ottawa in 1980 and 1981 (Williams et al', 1984), or in adipose tissue

obtained at autopsy from92 males and49 females in Ontario municipalitiesin 1984 (limit of detection,2.4 pgTkg) (Williams et al', 1988).

These results indicate that endrin is either absent or present at very lowlevels in the adipose tissue of the general population. It is therefore

surprising that Kaniz & Castello (1966) reported the presence of endrinin nine adipose tissue samples from Liguria, Italy, at a mean concentration

of0.93 mg/kg of tissue. Thehighestconcentration was2.49 mg/kg. Pavanet al. (1987) found endrin at 0.1 and 0.3 mglkg in 2 of 92 samples of

adipose tissue obtained at surgery from people living in the Province ofTurin, Italy. In areas where endrin has been used extensively, however,

such as India and the lower Mississippi, it has never been found in human

adipose tissue (Brooks, 1974).

One of 62 adipose tissue samples obtained at surgery from people in

Ciudad Juarez, Mexico, in L977-:78 contained endrin at 0.02 mgTkg(Redetzke et al., 1983).

5.2.2.2 Organs

[r samples of liver, kidney, gonad, and brain obtained from thegeneral population ofAlberta (Canada), no residue ofendrin was detected

ffadis et al., 1970).

5.2.2.3 Blood

No endrin was detected (limit of detection, 0.0 I mg/kg) in 4m0 bloodsamples from the general US population in 1976-80 (US E P A, 1983), orin areas where endrin has been used extensively, such as India and thelower Mississippi (Brooks, 197 4), or rn26 blood samples from the generalpopulation in Nigeria (Atuma, 1985).

5.2.2.4 Breast milk

Endrin was not detected inbreast milk in studies in theUSA in 1966-78 (Strassman&Kutz, 1977; Currie et al., 1979; Kutzetal.,1979a; Bamettet al., 1979), in El Salvador and Guatemala @e Campos & Olszyna-Marzys, 1979), in Belgium, Italy, andTheNetherlands (Kanitz & Castello,

83


1965; Hendrickx & Maes, 1969; Wegman & Greve, 1974), andin Japan(Yakushiji et al., 1979). No endrin was derected (< 0.01 mgflitre) in 50breast milk samples from morhers (aged 18-32 years) in Leiden, TheNetherlands, in 1969 (Tuinstra, l97l). Ir was found in one of l2 samplesfrom mothers ageA2l-31 in Pavia, Italy, in 1988, at a concentration of0.01 pglkg of whole milk, but nor in four samples collected in Crotone.southern Iraly (Bianchi er at., lggg).

5.2.2.5 Appraisal of exposure of the generat poputation

The occasional prescnce of row concentrations of cndrin in the air ofareas where endrin is used in agriculture cannot be consi<Jerecl a significantsource of contamination for the general public. The very low concenlrationsthat have been found in surface and drinking-water are also of littlesignificance for public healrh.

5.3

5.3.1

The source of exposure that may bc relevant is dietary intake. Apartfrom accidental c.ntamination, however, intake of cndrin by the gcneralpopulation in the countries examined has bcen and is still far bclow themaximum acceptable daily inrakc of 0.2 pg/kg body wcight csrablished bythe Joint FAOIVHO Mccting in 1970 (FAOAVHO, l97l). This applicsequally to the total intakc, when the intakc from dictary sourccs is a<idc<tto that from air and water.

Endrin has not becn dcmonstrated in the largc numbcr of samples oforgans, adiposetissuc, bl<xrd, andbreastmilk analysed indiflcrcnt countrics,even in arcas whcrc cndrin is or was used cxtcnsivclv.

Occupational exposure during manufacture,formulation and use

Manufacture and formulation

Endrin has not becn detccted in the blood, plasma, or urine o[ workersexposcd occuparionally ro cndrin (Hayes & Curtey, l96ft; Jager, 1970).Endrin was detcctcd in blood only after accidenral 'vcr-exposure. Jager(1970) estimared rhat the threshold level of endrin in the blcnd, belowwhich signs or symptoms of intoxication do not occur, Iies betwccn 0.05and 0.10 mg4itre. He estimated rhe half-life of endrin in thc blo<xl r. bc inths ordcr <>l'A lt.

84

i.3.2

EHC 130 : Endrin

The total exposure of workers in a manufacturing and formulationplant was estimated on the basis of determinations of the quantity of theendrin metabolite anri I 2-hydroxyendrin in urine. Urineof workers exposedto endrin for seven days hadconcentrations of up to 360 pglg of creatinine;no wrchanged endrin was found. Assuming an average daily excretion of1.5 g creatinineper day, the total daily excrettonof anti-L2-hydroxyendrinintheurinemay beup to540 pg. This gives aminimal absorptionof0.5 mgendrin, indicating that inhalation of duss and absorption through the skinmay be significant during occupational exposures in manufacture. It is notunreasonable to assume that, as in other species, approximately half of allthe endrin absorbed is excreted in the urine as anti-12-hydroxyendrin,since both endrin and this metabolite are present in the faeces of workers(Ottevanger &Van Sittert, 1979; Baldwin & Hutson, 1980 ). Thus, I mg/day may be the more accurate figure for exposure in this manufacturingplant. The concentration of anti-L2-hydroxyendrin in urine decreasedmore slowly than the concentrations of endrin in blood, with a half-life of55-:75h (Van Siuert, 1985).

Application

Endrin is applied in agriculture by high-pressure spraying with a handgun, spraying orchards with a power air blast or boom to control mice,dusting potatoes, sprayrng row crops, or application from aircraft. Thesemethods of application result in dermal and respiratory exposures.

The potential dermal and respiratory exposure of workers applyingendrin formulations in the field has been quantified in a few studies.Respiratory exposrue to endrin during spraying oforchards, high-pressurespraying of crops, and piloting of aircraft varied from 0.01 to 0.14 mg/h;dermal exposure during such activities was 0.01-1.64 mg/h. The activitythat caused the most exposure was dusting potatoes, which was associatedwith a respiratory exposure of 0.41 mglh and a dermal exposure of18.7 mg/h. Total exposure, calculated as a percentage of a toxic dose/[ = {dermal exposure (mgih) + [respiratory exposure (mglh)x l0l] + [dermallDro(mg/kg) x 70] x l00,was0.2l-1.57o@urham&Wolfe, 1962) (see Table 11). These figures show that although endrin isacutely highly toxic it can be used safely when reasonable precautions aretaken (Wolfe et al., 1963; Jegier, 1964; Wolfe et al., 1967; Hayes, 1975).

Endrin was not found in the blood of 20 pesticide sprayers or in19 controls in Choluteca, southem Hondwas (Steinberg et al., 1989).

85


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86

EHC 13O: Endrln

Appratsal of occupatlonal exposure

No residues were found in healthy workers. The range of thresholdlevels of endrin in blood below which no sign or symptom of intoxicationoccurs has been estimated to be 50-100 pflitre. The halflife of endrin inblood may be in the order of 21h following occupational exposure' Theconcentration of anti-L2-hydroxyendrin in the urine decreased moreslowly than the concentration of endrin in blood, with a half-life of 55-75h.

87

6. KINETICS AND METABOLISM

6.1 Absorption,distribution,andelimination

6.1.1 Laboratory animals I

6.1.1.1 Oral administration

Rat: One male rat was fed raC-endrin ar a level of 30 mg/kg of diet for8 days. About 6&-707o was excreted on the first day; after three days, thefaeces contained more then 807o of the administered radiolabel; by day 9,847o had been excreted; and there appeared to be a level of saturation after6-7 days of feeding. Only 0.5Vo was found in the urine. About 75-807o ofthe label in the faeces was in at least two different metabolites. The adiposetissue stored 34 mgkg, giving a srorage rare of about l0 (FAO/WHO,r97r).

After femalerats weregiven a single oral dose of raC-endrinat16,64,or 128 pgTkg body weight, excretion was rapid. The biological half-life ofthedosesof 16and64 pg/kgwas l-2 days;however,tharof 128 pglkgwasapproximately 6 days, showing thar excrerion of higher doses is slower(Korte et d., 1970).

Six CFErats of eachsex were treated with a single oral dose of 0.5 mglaC-endrin in arachis oil (approximately equivalent ro 2.5-3.0 mg/kg bodyweight), and the radiolabel excreted in urine and faeces was measured over3 days. The animals were then killed and the radiolabel measured intissues. A sex difference was noted in rherate of eliminationinfaeces:667aof the dose was excreted in 3 days by males and 377o by females; excretionwas slower in females but tended to increase daily between days I and 3.Small quantities ofradiolabel were excreted in theurine, females excretingthree times more than males. No radiolabel was found in exhaled air(Ilutson et al., 1975). The results are summarized in Tables 12 and 13.

Three rats of each sex were each given a single oral dose of 8 1rg t4C-endrin in peanut oil (by gavage) daily for I 2 days. A sready srare (ar whichthe excreted amount equalled the daily intake) was reached after about6 days. Females stored about rwice as nntch(T|Vo) as males (l4Vo).Theradiolabel was excreted mainly in the faeces: after the first 24h,70-:75Eoof the radiolabel was found in faeces as hydrophilic metabolites;

88

EHC 130: Endrin

subsequently, only metabolites were present. Four days after the last dose,males retained orliy 5Vo and females l5%o of the administered radiolabel(Klein et al., 1968; Korte et al., 1970).

Table 12. Rates of excretion of radiolabel by rats treated with a single oraldose of raO-endrin (percentage of radioactivity administered)

Urine

Dtl--DaytTtSFaeces

D-ari-"ay 2-D-il

MaleFemale

1 . 31 . 8

0.6 0.62.5 2.9

30.6 14.4 21 .22.3 10.7 24.2

Sex

Table 13. Recovery of radiolabel in rat tissues 3 days after a single oraldose of laC-endrin (percentage of radioactivity administered)

Urine Faeces Liver Kidneys Fat Skin Remaining Totalcarcass

Males 2.7 66.2 1.2 0.6Females 7.5 37.2 2.0 0.4

1 .7 2 .3 12 .28.0 4.0 28.1

86.987.2

Rabbit: A Dutch strainmalcrabbit was givcn twooral doscs of 4.7 mgtaC-endrin in olivc oil at an interval of 14 days. Between days I and 13,37o/o of thc lirst dosc was excrcted in the urine and 497o in the faeces: thesecond dose was eliminatcd similarly. By day 49,50qo had been excretedin urinc and 47o/o in faeccs. Faccal cxcrction was rapid, being almostcomplctc within 24 h, and consistcd virtually cntircly of unchangedcndrin. Thc urinc containcd only mctabolites (Bcdford et al., 1975a). Thecxcretion ol'mctab<>litcs in rabbits thus appcars to differconsidcrably fromthat in rats: approxirnatcly half o[ a dose of r{C-cndrin is cxcrctcd in theurinc ol' rabbits and approximatcly 2o/o in rats; endrin mctabolites arecxcrctcd in ral facccs ovcr scvcral days (aftcr a singlc oral dose), whcreasin rabbits faccal cxcrcl.ion is rapid, bcing almosr complcte within 24 h, andconsists virtually cntircly of unchangcd cndrin. The probable cxplanationis that thc rmrlccular wcight thrcshold for biliary secretion of anions is325+ 50 in rars and 475+50 in rabbits (Hirom et al. , 1972). Theglucuronidc and sulfatcconjugates of monohydroxyendrin have molccularwcights of 572 and 410, rcspcctivcly. Thercfore, conjugates of thc cndrinmctabolitcs arc climinatcd in thc bilc and faeccs of rats and in the urinc inrabbits.

89

6.1 .1 .2

K in et'rcs a n d metabo I i srtt

Dog: Three beagles were fed a dietcontaining endrin at a concentrationequivalent to 0. I mg/kg body weight for 128 days; rwo other animals wereused as controls. The concentration of endrin in blood was determined atweekly intervals. The time to reach a plateau in blood was less than 1 week,and no significant increase in the concentration of endrin in blood wasfound during this period. The average concentration between day 9 andday 128 was 4 pgllitre. The concentration ofendrin in eight organs andtissues of dogs killed 7 days after termination of exposure was < 0.2 mg/kg of tissue; except that the spleen of one dog contained 2.6 mgkg, andadipose tissue contained 0.2-0.8 mg/kg (Richardson er al.,1967).

I ntrave no u s ad m i n istrati o n

Mouse:Theconcentrations of endrin weredetermined in tissues fromgroups of five adult male CFI mice given endrin intravenously at 5 mgAgbody weight (-D) in dimethyl sulfoxide. The concenrrarions prior toconvulsions (about 10 min after injection) were approximately 60 mg/kgin liver, 20mgkg in brain and omental fat, and approximately 5 mg/itrein blood. The concentration in whole brain 15 min after an intravenousdose of 1.5 mglkg body weight (the dose thar caused araxia in 90Vo ofanimals; TDp was 9.4mgkg. No endrin was derected in rhe bile ofanimals with a bile fistula dosed intravenously with the TDro in samplescollected after 0.5, l, or 2 h (Walsh & Fink, 1972).

Ral: Male Holtzman rats with or without a bile fistula were given asingle intravenous doseof raC-endrin at 0.25 m/kg body weight. More than90Vo of the excreted radiolabel was found in the faeces of intact animalsoverthe 7-dayperiod afterdosing orinthebileof animals withfistulas over4 days. The mean total percentage recovery of administered radiolabet infaeces, urine, and carcasses was 97Vo from intact animals 7 days afterdosing, and94Vo from animals with a bile fistula 4 days after dosing (Coleet al., 1970). No unchanged endrin was found in bile; the maior merabolitew as an t i - 1 2-hydroxyendrin (see section 6. 2. I ).

Rapid excretion was observed inrats given two intravenous injectionsof laC-endrin at 0.1 mg/kg body weight at an interval of 4 days. Excretionof the radiolabel was exponential and occurred mainly with faeces; onlyhydrophilic metabolites were presenr. With a dose of 200 pglkg bodyweight, male rats retained 5.2Vo arrd females l2.l7o of rhe administereddose 20 days after the second injection. The biological half-life ofendrinafter a single intravenous dose of 200 pglkg body weight was 2.5-3 days

90

EHC 130: Endrin

in male rats and 4 days in females (Klein et al., 1968; Korte et al.,1970;Brooks, 1974).

Rabbit: When rabbits were given raC-endrin intravenously, theradiolabel was excreted mainly in the urine and only as metabolites. Aprobable explanation for the difference in excretion pattern after oral andintravenous administration is that much lowerdoses (micrograms comparedwith milligrams) were given intravenously (Korte et al., 197O).

11.2 Domestic animals

Twelve cows were fed hay from endrin-sprayed alfalfa containing anaverage of 1.9, 2.8, or 3.7 mgkg endrin; the average daily intake ofindividual animals ranged from 0.M to 0.11mg/kg body weight. Theaverage concentrations of endrin in the milk were < 0.05, 0.14, and 0.15mg/litre, respectively. When endrin dissolved in soya bean oil was fed to11 dairy cows, levels > I mg/kg body weight were required in order forsignificant quantities of endrin to be detected in milk (Ely et al., 1957).

Dairy cows (eightJerseys and six Guerrseys) werefeddiets containingendrin at 0,0.I ,O.25,0.75, or 2.O mgkg of diet for l2 weeks. No residueswere found (limit of detection, 0.01 mg/litre) in the milk of animals thatreceived 0.1 mg/kg, but up to 0.02 mg/litre was found in milk of animalsfed0.25 mg/kg andup to0.(X mglitre with0.75 mg/kg of diet; thehighestdose resulted in residues in milk of 0.1 mg/line. The endrin content ofbrain, heart, liver, kidneys, body fat, and muscles was < 0.1 mg/kg, butrenal fat contained up to 0.8 mgAg (Kiigemagi et al., 1958).

The concentrations of endrin in milk of cows given feed containingendrin at approximately 0.05, 0.14, and 0.30 mg/kg of whole feed for5 weeks were 0.004, 0.01, and 0.018 mgflitre, respectively (Williams etal., I 964). A steady (plateau) level in milk was reached after about I 5 days.

The concentration of endrin in the milk of dairy cows given feedcontaminated with relatively low levels of endrin rose rapidly within a fewhours to days and levelled off at a plateau characteristic for eachconcentration in the feed. The average milkdietratio for endrin was 0.07for feed levels of 0.05-O.3 mgftg of diet (Biehl & Buck, 1987).

Two lactating cows were fed raC-endrin for 2l days at an overalldietary concentration of 0.1 mgTkg of diet, which was considered to be

9 1

Kinetics and metaboli sm

comparable to the highest dose thatcows are likely toreceive incottonseedcake. Excretion of radiolabel in milk, urine, and faeces reached a plateau4-9 days after start of treatment. Approximately 37o of theradiolabel was.excreted in milk, 657o in urine, and ?-UVo in faeces. Unchanged endrin wasnot found in urine, but about 307o of the radiolabel in faeces and all of the0.003--0,006 mg/litre found in milk was endrin. The concentration ofendrin equivalent residues was 0.001-0.002 mglkg in meat and 0.02-0. 10 mg/kg in fat; most of the radiolabel in fat consisted of endrin (B atdwineraL.,1976).

Steers, hogs, and lambs fed diets containing endrin at 0, 0.1, 0.25, or0.75 mg/kg of diet for 12 weeks had residues of < 0. 1 mg/kg in red meat,liver, and kidneys and of 0.02-0.2mgkg in body fat. Feeding endrin at2 mgkg of diet to steers for 12 weeks resulted in residues of 0.9 mg/kg infat and 0.2{.3 mg/kg in red mear, liver and kidneys (Terriere et al., I 958).The biotrarsferfactors for endrin in beef and milk were directly proportionalto the octanol-water partition coefficients, while the bioconcentrationfactorforendrin invegetation was inversely proportional to the square rootof the octanol-water partition coefficient (Travis & Arms, 1988).

S ix weeks after the start of feeding seven Delaw are X New Hampshiremale chicks andeight weeks after thestartof feeding sevenWhiteLeghornpullets a diet containing endrin at 0. I mg/kg, the residues in eggs and meatwere < 0.I mg/kg and that in fat, 0.6 mgAg. At a dietary level of 0.25 mg/kg, the residue levels were 0.24.3 mgftg in eggs, 0.1mg/kg in breastmeat, and about I mg/kg in fat. With 0.75 mg/kg of diet, the levels wereO.4mglkg in eggs, 0.24mgkg in breast meat, and 3.1mg/kg in fat(Terriere et al., 1959).

raC-Endrin was administered daily in com oil ingelatin capsules ro sixIaying hers at a concentration equivalent to 0.13 mg/kg of total diet for2l weeks. Ingestion and elimination in eggs and excreta were almostbalanced after about 16weeks. The residue levels in eggs were 0.11-0. I 8 mgTkg and were found in the yolk; none of the known metabolites wasdetected. The levels of endrin equivalent were about 0.01 mgTkg in breastmeat and 0.1mg/kg in leg meat; higher levels were found in the liver(0.a7 mglkg), kidneys (0. 17 mC/kg), and fat ( I mg/kg). The residues wereaccounted for by unchanged endrin, except in the liver and kidneys, wherepartprobably consisted of polarmetabolites. About 5(9o of the administeredradiolabel was excreted in the faeces, lo9o of which was in unchangcdendrin (Baldwin et al., 1976),

92

.1.3

tI

EHC 130: Endrln

Human beings

The concentrations of endrin in the blood of workmen exposed toendrin were generally below the level of detection: endrin was not foundin plasma (< 3 ltgtitre) or f at (< 0.03 mglkg) of workers exposed ro endrinfor an average of 88 days (Hayes & Curley, 1968). No endrin was foundin the blood of healthy people working in an endrin marrufacruring plantbetween 1964 and 1970, at an initial limit of derection of l0 pg/itre,improved after 1965 to 5 pgllitre (Jager, 1970).

Residues of endrin have been found in blood only in individuals withsigns ofrecent intoxication or who have recently had excessive exposure(see section 9.2.2). Endrin appears to be eliminated rapidly from rhehuman body.

Sysfems in vitro

Isolated liver preparations from Holtzman rats were perfused with asolution containing laC-endrin at 0.003 mg/ml. Within I h, 50Vo of theradiolabel appeared in the bile; and in 6 h, more than 907oof thc toral labelwas found (Cole et al., 1970). With rhc same dose, radiolirbcl appeareA2-l2 times faster in the bile of livers isolated from male rats as in that of liversfrom females, which may account for the lower toxicity and lower storageof endrin in adipose tissue in male rars (Klevay, 197 I ). After perfusion ofalbino rat liver with a physiological solution conraining 40 pg of taC-

endrin, both endrin and hydrophilic metabolites were found (Altmeier &Korte, 1969).

Biotransformation

lnformation on the metabolism of endrin up to 1967 was reviewecl(Soto & Deichmann, 1967; Brooks, 1969).

Experimental animals

A number of investigations hive been carried out since 1970 toelucidate the identity of several metabolites of endrin in rats (Baldwin etal., 1970; Richardson et al.,1970 Hutson er al., 1975: Bedford & Hutson,1976), rabbits (Bedford et al., 1975a; Hurson, l98l), cows and chickens(Baldwin et al., 1976). The l2-hydroxy derivative was reporred ro be

1.4

.2

I

,,2.1

93

Klnetics and metabolism

present in the faeces ofrats (Baldwin et al., 1 970), and the hydroxyl groupwas assigned tentatively as.ryn to the epoxide ring. The stereochemicalconfiguration was subsequently shown to be anti to the epoxide group(Baldwin et al., 1973), and this configuration was confirmed by thesynthesis of anti-l2-hydroxyendrin (also called 9 -ant i-hy droxyendrin)(Bedford & H arrod, 197 3; Bedford et al., I 986a). The chemical structuresof these compounds are shown in Figure 2; the chemical names are givenin Annex I.

Formation of anti-l2-hydroxyendrin (/fl, togcther with its sulfateand glucuronide conjugates, is considcred to bc the major route ofmetabolism of endrin. Fourothermetabolites have bccn reported, but thcirconcentrations are generally smallcr than that of anti-I2-hydroxyendrinand its conjugates. These four metabolites are syn-t2-hydroxyendrin (//;

tentative identification), 3-hydroxyen drin (lV; synthesized and structureconfirmed by Bedford et al., t 986b), I 2-ketoendrin (l|, and the product offormal hydroxylation of endrin, the 4,5-trans-dihydroisodrindiol (V1;

tentative structure). The trans-diol (V1) is a minor metabolite in both ratsandrabbis; itmay beformedvia anoxidation-reductionpathway involvingintermediatcs of the corresponding ketol (Vfl. Each of the hydroxycompounds is also excreted partly as its sulfate or glucuronide in the urineof animals (Bedford et al., l975a,b; Hutson e t al., I 975).

The threc monohydroxylatcd derivativcs of cndrin,.tyn- and anti-|2-hydroxyendrin (ll and IID md 3-hydroxycndrin (/V), are the products ofthe action of liver microsomal monooxygenascs on endrin (Bcdford &Hutson, 1976). These alcohols are also conjugatcd to glucuronides andsulfates to some extent in the liver. Comparative mctabolic studies with ratliver microsome preparatiolts have shown th atlrree syn-12-hydroxyendrin,but not its free anri-isomer, is the precursor of l2-kctoendrin (l/) (Hutson

& Hoadley, 1974).

Rats cxhibit a scx difference in thc rate o[ mctabolism. The majormctabolite in animals of cach scx is anli-12-hydroxycndrin, which isexcrctcd via thc bilo as thc glucuronidc; this undcrgocs enterohepaticcirculation and is eliminated as the aglyconc in thc facccs, togethcr withtwominormetabolites,3-hydroxyendrin and 4,5-trans-clihydroisodrindiol.Male rats produce the metabolite at a higher rate than do fcmalcs. Themajor urinary mctabolite in male CFE rats was l2-kctoendrin, whilefemales excreted mainly anti-12-hydroxycndrin O-sulfate. Endrin and thelipophilic metabolite 12-ketoendrin were the major compouncls found inthe organs and tissues of male and female CFE rats 3 days aftcr a single oral

94

EHC 130: Endrin

-xo

od

oo

co

.oo

o

Eo'x

.9

coo=N

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95

Kinetics and metabolism

dose of endrin, but the ratio of endrin: l2-ketoendrin was 2/l infemales andl/8 in males. Thus. I 2-ketoendrin corstituted most of the radiolabel in theliver and kidneys of males and endrin that in the kidneys of females(Hutson et al., 1975; Hutson, 1981).

The metabolism of endrin in rabbits is superficially different from thatin rats. The major metabolite is still anti-l2,hydroxyendrin, but it isconjugated with sulfate and eliminated in the urine. Some syn-12-hydroxyendrin was also detected as its sulfate in urine, and perhapsconjugation and elimination prevented further oxidation to 1 2-ketoendrin.The respective glucuronide conjugates were also eliminated in the urine,as were the glucuronides of 3-hydroxyendrin and the 4,5-trans-diol (Vl(Bedford et al., 1975b; Hutson, 1981).

Studies with raC-endrin in lactating cows showed thar rhe residues inmilk and body fat consisted ofunchanged endrin, although traces of 12-ketoendrin were consistently found in fat. As itrats, anti-t2-hydroxyendrinwas the major metabolite in urine and faeces, the urine being the majorexcretory route, as in rabbits. l2-Ketoendrin and syn-12-hydroxyendrinwereminormetabolitesincow urine (Baldwinet al., 1976). Thus, althoughthe metabolic pathways of endrin in cows are qualitatively similar to thosein rats and rabbits, quantitative differences are seen in faecal and urinaryexcretion.

ln hens, only endrin was found as a residue in meat, fat, and eggs.Unchanged endrin accounted for about l1vo oftheradiolabel in excreta,and the major metabolite was anti-Iz-hydroxyendrin and its sulfateconjugate. No 12-ketoendrin was detected in tissues, eggs, or excreta. Themetabolism of endrin in hens is fundamentally similar to that in rats,rabbits, and cows, except that they produce neither syn-L2-hydroxyendrinnortherelated 12-ketoendrin. Therateofmetabolism,however, wasmuchlower than in cows (Baldwin et al., 1976). The absence of l2-ketoendrinin birds was confirmed in a study of four species killed by endrin (Stickeletal., 1979). Hutsonetal. (1975) suggested rhat the acutetoxicity of endrinin birds is not associated with the formation of l2-ketoendrin.

6.2.2 Human beings

No endrin was found (limit of detecrion, 0. (X) I 6 mg/itre) in 14 s amplesofurine from workers exposed to aldrin, dieldrin, and endrin, even thoughworkers with a complete work history had been exposed to endrin for an

96

2.3

EHC 130: Endrin

average of 2160 h (Hayes & Curley, 1968). Endrin was not detected inurine from five men and five women (Cueto & Ha54es, 1962; Cueto &Biros, 1967). No unchanged endrin was found in the urine of Dutchworkers.exposed to endrin, but it occurred in the faeces (Jager, 1970;Baldwin & Hutson, 1980).

Neither 3-hydroxyendrin nor the diol was detected in urine or faeces(Hutson, l98I). anti-L2-Hydroxyendrin waspresent in theurine of workersexposed to endrin, and the glucuronide was found in the faeces.Concentrations of up to 0.36 mg,/g of creatinine were found in urine after7 days, accompaniedby asharprisein thelevel of o-glutaric acid (excretedin the urine of mammals as a metabolite of D-glucuronolactone [Marsh,19631), indicating that liver enzyme induction may have occurred' Thelevels tended to decrease over the weekend (Ottevanger & Van Siltert,1979). Endrin, anti-12-hydroxyendrin, l2-ketoendrin, and the beta-glucuronide of anti-|2-hydroxyendrin were not found in the blood ofworkers at a Dutchplant for themanufacture of endrin (limit of detection,Z1tgllitre). Both endrin and anti-72-hydroxyendrin we,re found in thefaeces, and all urine samples contained the beta-glucuronide of anti-|2-hydroxyendrin up to a concentration of 0.14 mg/litre as anti-|Z'hydroxyendrin (Baldwin & Hutson, 1980).

Hydroxylation at anti-C-|Z is relatively rapid and accounts for therapid metabolism of endrin. Even syn- 1 2-hydroxyendrin is hydroxylatedrapidly at its anti-C-I2 position, affording l2-ketoendrin (Hutson, 1981).

As neither endrin nor its metabolites were found in the blood ofexposed, healthy workers, exposure can be measured by determining dzti-l2-hydroxyendrin in urine. A quantitative relationship between exposureto endrin and the concentration of this metabolite cannot be established.however, owing to lack of data.

Microorganisms

In mixed anaerobic microbial populations developed using inoculafrom soil, freshwater mud, sheep rumen, and chicken litter, endrin (likeother cyclodiene compounds) was monodechlorinated at the methylenebridge carbon atom. Neither endrin nor any other compound was furthermetabolized. The 10 obligate anaerobic bacteria that made up the mixedpopulation were subsequently isolated in pure culture. Of these, onlyClostridium bifermentans, C. glycolium, and other Clostridium species

97

6.2.4

Kinetlcs and metabolism

were capable of dehalogenation, but at arate that was much slower thanthat of the mixed population (Maule er al., 1987).

Plants

Three experiments were carried out on tobacco plants. In the firstexperiment, 2.08 mg of raC-endrin were applied to the leaves with freeaeration during the experimental perio<I. In the second test, the same dosewas applied but with little aeration; and in the third, plants were exposedto l.(X mg of taC-endrin with little aeration. An initial residue level of 50-100 mg/kg was foundon leaves inall threeexperiments, but, subsequently,less residue was found on plants with free aeration. Six weeks aftertreatment, 30-47 Vo of radiola&l was recovered in residues, which consistedof endrin and hydrophilic subsrances (Weisgerber et al., 1969; Donoso era1.,1979).

Theleaves of cottonplantsweretreated with4.2 mgof |aC-endrin, andthe application was repeated after 2 and again after 6 weeks, ar which timeparathion was also applied. At harvesr, two-thirds of the radiolabel hadevaporated, and the rotal residue in cotton seed was A3T mgkg. Endrinand two groups ofdegradation products were found in the plants; one ofthese products (possibly delra-ketoendrin) was only slightly morehydrophilic than endrin, and the orher was very hydrophilic. Most of themetabolites were found on the surface of the leaves. When delta-ketoendrinwas applied to white cabbage, it disappeared more slowly rhan endrin, wirhthe formation of hydrophilic metabolites (Korte, 1969).

98

: .1

7. EFFECTS ON ORGANISMS IN THEENVIRONMENT

Microorganlsms

The interactions of halogenated pesticides and microorganisms havebeen reviewed extensively (Pfi ster, 1972).

In tlrree Willamette valley soils (USA) treated with endrin at 0, I or10 mglkg, no effect was found 30 days after application on the functionand activity of the microbial population, the decomposition of nativeorganic matter, the transformation of native soil niuogen, ammonificationof peptone, or nitrification of ammonium sulphate (Bollen & Tu, l97l).Even at an annual application rate of 5 lb/acre (5.6 kg/ha) for 5 years, noeffect was seen on the numbers or kinds of soil frurgi, the numbers ofbacteria, the decomposition rate of organic matter (measured by CQproducrion), or the oxidationof ammonium to nitrate (lvlirtinet al., 1959).

Endrin at a concentration of 100 mg/kg of soil had no effect ondenitrification in soil under anaerobic incubation for 5 days at 30 oC or inan isolated denitrifying bacterium (Bollag & Henninger, 1976), Aconcentration of 1000 mglkg had no effect on methanogenesis, sulfatereduction, or carbon dioxide evolution in anaerobic salt-marsh sediments(Kiene & Capone, 1984).

The growth rates of two strains of blue-green algae were decreased inthe presence of endrin at a concentration of 0.29 pgnitre (Batterton et al.,1971), and the productivity of many forms of natural phytoplankton inestuarine waters was decreased by 464o when they were exposed to I mg/litre (Butler, 1963).

1.2 Aquatic organlsms'.2.1 lnvertebrates

Acute toxicity of endrin to invertebrates is given in Tables 14 and 15.

A static systemwasused to study the toxicity of endrin to a polychaeteworm (Nereis virew) in water and sediment, in which sea water orsediment (containing 17Vo sand, 837o clay, and 24o organic carbon) was

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present at a temperature of 9-10 oC for 12 days. None of the worms in seawater died after exposure to endrin at 0. 1 I mg/lite f or 1 2 days, but two offive worms exposed to 28 mg/kg in sediment died in this period (Mckeseet al., 1982).

The mean 96-h LC, for the oligochaetes Sry lodrilus heringianus andLimnodrilus hoffmeisteri exposed to sediment from Lake Michigancontaminated with taC-endrin was 2588 t1974 mg/kg dry weight ofsediment infour assays and 2725 + 955 mglkg in two assays. The toxicityto L. hoffnwisteri appeared to bereduced in the presence of S. heringianus.The 96-h EC, burrowing avoidance values were 15.3-19 mg/kg for S.heringianus and 59 mg/kg of sedimenr for L. hoffmeisteri (Keilty et al.,1988a).

Sediment reworking by I,. hofftneisteri alone and with.S . heringianuswas measuredbymonitoring theburial of a 13?Csmarkerlayer in sedimentsdosed with tT- and raC-endrin ar concenrrarions of 5.5-81 400 pgTkg ofdry sediment. With low endrin concentrations, the marker layer burial ratedid not suggest stimulation of reworking by either L. hoffnuisteri or S.heringianus. At higher concentrations, the reworking rates were equal toor slower than control rates at the beginning of the experiment butdecreased thereafter. The presence ofS. heringianus appeared to enhancethe reworking response of L. hoffnuisteri. A reduction in the post-experimental mortality and an increase in the dry w eight of L. hoffneisteriin tests with the two species implies thatL. hofftttcisrerj benefits from thepresence of S. heringianzs, although the reverse was not observed. Highconcenffations of endrin in the upper 3 cm of the final sediment showedthat the worms had transported the contaminant upward. Thebioaccumulation factor for S . he r ing ianw ranged from 9. 7 ro 43.8 and wasconsistently three to four times greater than that for L. hoffmeisteri (1.7-13.6) (Keilty et al., 1988b).

The reworking rates of S. heringianzs in microcosms containingsediments dosed with raC-endrin at3.l42 000 pg/kg of dry matter weremeasured at l0 oCbymonitoring a r3tsmarkerlayerburied incontaminatedand uncontaminated microcosms. Alterations in reworking rates wereobserved at endrin concentrations 5.5 orders of magnitude below the LC*of 1650 mgkg. At the lower concenrrarions, a possible stimulatory effecion the marker layer burial rare in the first 300-600 h was followed by asignificant decrease relative to the controls. At the higher concentrations,the rates were equal or slower during the first 600 h and decreased

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EHC 130: Endrin

dramatically in the last 600h. Mortality was 9.3-28Vo at 11500 and42CfJ0 pg/kg and 0-6.7Vo at all the other concentrations tested, includingcontrols. The dry weights of the worms at the end of the experiment wereinversely related to the high concentrations. The bioaccumulationfactorsrangedfrom34 to 67 on thebasis of gramsof dry organism tograms of drysediment (Keilty et al., 1988c).

The effect of addition of endrin at 50 mg/kg dry weight of sedimentonprotein utilization by S. heringianus was examined on days 4, 8,20, 28,39, and 69. A slight increase in the relative percentage ofprotein to totalbody weight was observed, but the authors concluded that estimation oftotal protein is not a useful measure of sublethal responses (Keilty &Stehly, 1989).

The total organic carbon content of sediment had little apparent effecton the toxicity of endrin in the freshwater amphipod Hya lella azteca.Tbel0-day LCro for endrin in sediment (dry-weight basis) was 4.4 pg/itre at3.OVototalorganic carbon and 6.0 pgllitre at77.2Vo carbon(Neb6ker et al.,1989).

The ECrus in thc green sea urchin (S to ngy loce nt rolus droe bac hie ns is),the purplc sca vchin (S . purpuralus), the red sea urchin (S.y'an ciscanus),and the sand dollar (Dendraster excentricus) were 103-441 pg/itre forspcrm in a static system and 221-> 362 pglitre foremb'ryos in a continuousfl ow of sea water(tempcrature,8.2-8.4 oC; salinity, 30.0partsperthousand;pH 7.8-8. I for the sca urchins and I 2.5-13.0 "C, 30.0 parts per thousand,and pH 8.0-8.1 for sand dollar embryos), both with an bxposure time of120h. In a larval test of static exposure of Dungeness crab (Cancermagister), the ECrowas 2.0 pgllitre (Dinnel et al., 1989).

Endrin was tested at 0, 0.025, 0.05, 0.1, 0.25, 0.5, 1.0,2.5,5.0, andl0 mgflitre for its effects on emb'ryos of the American oyster (Crassostreavirginica) and their larvae. Fertilized eggs were studied after 48 h, andsurvival and growth of veliger larvae were studicd in 2-day old larvae andin I arvae kcpt f<r a furthcr I 2 day s at A oC. The results vari ed corniderably.The cstimated conccntration that would cause an approximately 50oloreduction in thc numbcr of eggs that dcvelop into normal straight-hingelarvac, calculated by interpolation from the data, was 0.79 pglitre and thatat which 5OVo of thc larvae survived was > 10.0 mg/litre (Davis & Hidu,1969).

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Etfects on organlsms in the envlronment

In the mysid shrimp Mysidopsis bahia, expsel,for the complete lifecycle, acute lethality (over 96 h) was observed with endrin at l2O ngflive;increased oxygen consumption was measurable within 24 h of exposure.The lowest-observed-effect level for chronic lethality was 60 ngllitre; sub-lethal effects on growth (reduced by day4 of exposure) and oxygenconsumption (increased by day 10 of exposure) were observed beforedeath(over20 days). Reducedreproductivecapacity (assessedasproductionof young) was observed at 30 ng/line over 20 days-the time to fullmaturity (McKenney, 1986).

Behavioural changes wereobserved in ston eflies (P tero rwrcys dors ata)within 4 days of exposure to 96.17o endrin ar 0.07 1tgllitre and in caddisflies(Brachycentnts americanzs) at 0.15 pgllitre. The 28-day LCro was <0.03 pg/litre for caddis flies and 0.07 pgAitre for sroneflies (Anderson &DeFoe, 1980).

7.2.2 Fish

7.2.2.1 Acute toxicity

Endrin is highly roxic for both freshwarer and marine fish. Theavailable data are summarized in Tables 16 and 17.

7.2.2.2 Short-term toxicity

Channel catfish(lctalurus punctatus) were exposed continuously torenewed solutions of endrin in water at 15 and 22 "C. Measured endrinconcentrations of 0.25--0.30 Fgllire were found to be acutely toxic to rhefish within l0 days or less. None of the fish survived blood concenrrationsexceeding 0.28 mg/litre, a well-defined threshold concentration of endrinin blood, and none died at less than 0.23 mglitre. The concentration ofendrin in the blood of fish exposed to lethal concentrations in water forperiods insufficient ro cause death were markedly lower than that in fishthat died from exposure to the same water (Mount et al., 1966).

The 28-day L C * for 96. l%o eldrin in bullhea ds (l c talur us melas) was0.10 ttg/litre (Anderson & DeFoe, 1980).

In larval fathead mirmows (<Uh old) exposed continuously toendrin (987d for 28-30 days in a flow-rhrough system, growrh was rhemost sensitive parameter. A 48-h exposure to 0.62 pg/litre caused significant

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reduction in growth, and survival was reduc ed at |.21 pgllitre; with a72-h exposure, growth was reduced at 0.63 pgnirre, and all fish died atl. 15 pgaine. conrinuousexposureto0.38 pg/itrefor30 dayssignificantlyreduced growth, and all fish died at 0.73 ltg[itre (Jarvinen et al., lggg).

Sheephead minnows (Cyprinodon variegatus) were exposedcontinuously for 23 weeks to endrin from the embryonic stage throughhatching, until adulthood and spawning. The average exposureconcenrrarions were 0 (control), 0.02i,0.077,0.12, 0.31, urd0.72 1tg/litre, The resultant progeny were monitored to determine effects on theirsurvival, growth, and reproduction. Embryos exposed to 0.31 and 0.72pgllitre hatched early; all fry exposed to O.'l2pglitre died by day 9 ofexposure. At 0.31 lrg/itre, fry were initially stunred and some died.Survivors seemed turaffected until maturity, when some females diedduring spawning; fewer eggs werefertile, and survival of exposed progenywas decreased. No significant effect was observed throughout the lifecycle at an exposwe concenrrarion of 0.12 pgllirre (Hansen etal.,1977).

Endrin was resred in flagfish (,/oidanellafloridae) at0.21,0.29, and0.39 pg/litrefor30 days. only thehighestconcentrariondecreased survival,and the two highest dose levels affected the mean number of eggsproduced (Hermanurz et al., 1985).

7.2.2.3 Studies of resistance

Populations of mosquito fish (Gambusia affinis) developed highlevels of resistance to endrin and other cyclodiene insecticides

"r . t"rult

of inadvertent exposure to agricultural sprays. Susceptible fish (male)showed a LCro of 8.3 mg/litre and resistant fish, 16l mg/titre. Geneticcrossing studies show that endrin resistance is inherited as a single,autosomal, intermediate gene (Yarbrough et al., 19g6).

,. Pesticide-susceptible and -resistant mosquito fish were exposed toraC-endrin at 20 or 1000 pgflitre, and liver and brain were assayed todetermine any difference in distribution, uptake, and nerve bindingpattems @abacher & Chambers, 1976). The resulrs are summarized inTable 18' Endrin was taken up faster by b'rain and liver from susceptiblefishthanresistantfish. Inresistantfish,atleastatahighlethalconcentration(1000 trg/litre), endrin entered the brain slowly and accumulated in theIiver, suggesring a more efficient blood-brain barrier in resistant than insusceptible fish. Extraction srudies provided some evidence that endrin

1 1 4

EHC 130: Endrln

binds more readily to nonessential protein complexes in the nervous tissue

of resistant fish, consequently decreasing the amount ofrendrin available

to produce a toxic effect.

Table 18. Mean quantities of endrin (in mg/kg tissue) in brain and liver ofsusceptible and resistant mosquito fish

Genotype At 20 pg/litre At 1000 pg/litre

Brain Liver Brainliver Brain Liver Brain:liver

Susceptible 16.98 33.28

Resistant 8.83 16.84

Susceptible: 1.90 1.90resistant

149.31 160.27 0.93

57.52 353.42 0.16

2.60 0.45 5.80

0.51

0.52

1.00

.2.2.4

Cell membrane fractions from resistant mosquito fish bound more

endrin than those from susceptible fish, and mitochondria from the liver of

the resistant genotype bound less endrin than those from susceptible fish.

Differences in endrin uptake, retention of endrin by brain cell membranes,

a blood-brain barrier, and a structural difference inmyelinmayaccountfortheresistance of somemosquito fish toendrin (Wells &Yarbrough' l9?2)'

In resistant and non-resistant Populations of golden shiner(N o te migo nus c ry s o leucas), blue gill srurfi sh (Le po mis nwc roc hir us), and

green srurfish (Lepomis cyanellas), the median tolerated limit at 36 h was

3.0, 1.5, md 3.4 pg/itrc for non-resistant strains and 3 I 0, 3fi), and I 60 pgl

litre for resistant fish, respectively (Ferguson et al., 1964)'

lnteraction with other chemicals

The joint action of endrin with malathion on mortality in flagfish(J ordanetla floridac) corsisted of enhanced effects at concentrations that

had no effect when the substances were tested individually. The effects of

thc mixture on growth followed a simple additive model. Malathion did not

modify thc effect of cndrin on egg production. In a separate test, malathion

did not affcct the uptake or elimination of endrin (Hermanutz et al', 1 985 ).

ln a study of the interaction between the accumulatidn andeliminationof taC-cntlrin and taC-DDT in mosquito fi sh (G arnbus ia aff i nis), fi sh about

1 1 5

Etfects on organisms in the environment

4 cm long were exposed to a nominar concentration of 3.94 nM endrin orDDT, or to a mixture of the compounds. prior exposure to DDT for 4 hgenerally reduced the accumulation of endrin in serun1 gall-bladder, andwhole bodies, whereas prior exposure to endrin for 4 h had little effect onDDT accumulation. Simultaneous exposure to DDT and endrin reducedthe accumulation of DDT in the gall-bladder over the 4 h of exposure andin the whole bodies during the first hours, and it reduced the acCumulationof endrin in gall-bladder and in the whole body. Endrin revels in fishexposed subsequently only to DDT or DDE were significanrly higher ingall-bladder and were reduced in the whole body over 4 h. The interactiorsobserved may be the result of competition for and/or displacement ofinsecticides from mutual binding sites (Denison er al., lggj).

Ia a study of the relative binding and competition berweenorganochlorine pesticides for serum binding sites, incubation with serumfrom mosquito fish led to theii associationprimarily with the vitellogeninllipoprotein and albumin fractions. preincubation of serum with endrinsignificantly reduced thequantity of 3H-DDT rhat was boturd subsequently,wtrile the reverse was not observed. Although the reason for the apparenrquantitative decrease in binding is unknown, this phenomenon may be oftoxicological importance (Denison & yarb,rough, l9S5).

7.2.2.5 Special studies

_^ -Fingerlings of carp (Cyprinus carpio) exposed to endrin at the LCro(0.0065 mgAg) for 24hshowed clear inhibirion of cr-amylase activity i'rithe liver @aua & Ghose, 1985).

A group of A0 rainbow trout (Salmo gairdneri) were exposed toendrin at 0.12-0.15 pgllirre for 30 days; one unrreared and one solvenrcontrol group were used. On day 30, l0 fish from each group weresacrificed and examined for the ability of peritoneal macrophages tophagocytize latex beads. The remaining fish were immunized wrttr-tO pgof Yersinia rrckeri o-antigen and exposure to endrin continued. Assays ioimigration inhibition facror, plaque forming cells, and serum agglutinationtitre were performed 2, 14, and 30 days after inoculation, and ,"rum *u,collected from all fish to determine the cortisol concentration. Exposure toendrin had no effect on the phagocytic ability ofperitoneal macrophages,but theresponses in the three assays were significantly reduced incomparisonwith the control values. Serum cortisol concentrations were significantlyelevated in the endrin-treated fish. The study did not, however, elucidate

1 1 6

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the mechanism of immune suppression, other than showing that a stressresponse had occurred (Benneu & Wolke, 1987a). In another study,tlerefore, control fish were fed cortisol at 20 mgkg and metyrapone at35 mg/kg body weight, and endrin-exposed fish received meryrapone at35 mgkg body weight per day in the diet. The fish thar received corrisolhad significantly reduced responses in all three assays; but in the endrin-exposed fish that received metyrapone, the migration inhibition factorresponse was completely restored, the plaque forming cell response wasrestored to 6lvo, and serum agglutination titres to 692o. These resultsindicate that elevated senrm cortisol concentration plays a central role inrepressing the immune response (Bennett & Wotke, 1982b).

The concentrations of serum glucose, liver and muscle glycogen,cortisol, protein, and cholesterol were determined in carp (Cyprinuscarpio) exposed ro endrin at 2 tlg[itre for 6, A, and 72 h. Only theconcentration of cortisol in serum was clearly decreased (Cluth & Hanke,1985).

7.2.3 Amphibla

The acute toxicity of endrin to amphibiars is summarized in Table 19.

7.3 Terrestrialorganlsms

The acute oral toxicity of endrin for terrestrial animals is high. Theavailable LDro values are summarized in Table 20.

7.3.1 Honey bees

The 48-h LDro of endrin in worker honey bees (Apis mc llifera) usinga dusting technique was 2.O2 +tghee (Arkins et al., 19?3). The LDro forbees after contact was 0.65 tlg/bee, and the acute oral LDro was 0.46 pglbee (Oomen, 1986).

1 1 8

EHC 130: Endrln

Table 20. Acute oral LDros of endrin for terrestrial species

Species LD*(mflkg body weight)

Reference

Blrds

Mdlard(Anas platyhynchos)

Pioeon(dolumbia livial

Pheasant(Phasianus colchicus)

Sharo-tailed srouse(Pedoecetei phasianellusl

Califomia quail

Redrvinqed blackbird(Agelaiis phoeniceus)

Starlinq(Sturnis vulgaris\

Quail(Coturnix coturnixl

llammals

Bio brown bat(Fptesicus tuscus)

Pine mouse (Microtwpttymys pinetorum,

5.6 (2.7-11.7)

2.0-5.0

1.8 (1.1-2.8)

1.06 (0.552-2.04)

1 . 19 (0.857-1 .65)

2.37

2.37J.16

4.22

5-€

2.6/19.O1.3/36.4(su scepti ble/resistant)

Hudson et al. (1984)

Schaferetal. (1983)

Luckens & Davis (1965)

Petrella et al. (1975)webbe ta l . ( 1973 ) '

,3.2 Birds

.3.2.1 Acute toxicity

The LDros of endrin for some bird species are given in Table 20.

.3.2.2 Short-term toxicity

Groups of40 one-day-old quail were fed endrin at dietary levels of 0,0.5, 1,5, 10,20, or 50 mg/kg of diet. Survival was adversely affected in alltest groups, and there were no survivors beyond two weeks among birdsfed l0 mg&g or more. Food consumption was abnormally low, andsymptosrs involved lack of muscular coordination, tremors, and occasional

1 1 9

Eftects on organisms ln the envlronment

convulsive movements. Similar results were obtained in 40 one_day_oldpheasants fed endrin at dietary levels of 5 or 20 mg/kg, none of whichsurvived beyond 8 days @ewiu, 1965).

Groups of 20 seven-day-old chicks were unaffected by diets containingendrin at 0, L5, or 3 mg/kg. When the concentration was increased to 6 or12mgkg, the birds became highly excitable and failed ro gain weight incomparison with controls. The survival rates over a l2-week period were85 and 5%, respectively, compared with 1007o in the controls (Sherman &Rosenberg, 1954).

The LCro values for 2-3-week-old hobwhite quail (Colinusvirginianus), Japanese quall (Coturnix coturnit japonica), ring-neckedpheasants (Phasianus colchicus), and mallards (Anas platyrhyrchos) (g_13 birds per group) fed endrin in their diet for 5 days followed by 3 daysof untreated dier., were l4-22mg\g diet (Hill et al., 1975; Hill &Camardese, 1986).

7.3.2.3 Sludies of reproduction

In a study of reproduction in pheasants, a diet containing endrin atl0 mg/kg reduced egg production and chick survival; diets containing upto 2mgkg did not affect egg production, fertility, hatchability, or chicksurvival (Dewiu, 1965).

Groups of five female and two male mallard ducks (Anasplatyrhyncho.r) were administered diers containing endrin at 0, 0.5, or3.0mg/kg for a l2-week oviposition period. Egg production was noraffected. The eggs were incubated, and infertile eggs, embryo survival,and hatchability were measured. Fertility and hatchability were notaff'ectcd, although a 9.6Vo drop in embryo survival was observed in thegroup that had received the highest dose. Endrin residues in body fat were3.4mgkC of tissue in the group rhar received 0.5 mg/kg and 19.3 mg/kgin the group thar received 3.0 mg/kg. The concenrrations were higher infemales than in males. The endrin residue levels in eggs were nonedetected in the conrols, 0.43 mg/kg in thc group fed 0.5 mg/kg, arf,2.75mg/kg in the group fed 3.0 mgAg (Roylance et al., 1985).

Three groups of 27 pairs of mallards were fed endrin at 0, l, or 3 mg/kg of dry duck mash from December to the summer to investigate theinfluence on reproduction and health. Birds fed I mg/kg reproduced as

120

EHC 130: Endrin

well as the controls; they had significantly greater success in hatchingfertile eggs than did those fed 0 or 3 mg/kg and their clutches hatchedearlier (not significantly) than those of birds fed 3 mgkg. Endrinaccumulated in eggs to a mean level of 1. I mg/kg (wet weight) in the groupfed I mgltg and 2.9 mglkg in the group fed 3 mg/kg. The concentration ofendrin in adipose tissue was four to seven times higher than that in eggs(Spann et al., 1986).

9.2.4 lnteraction with other chemicals

The toxicity of combinatiors of cNordane and endrin was studied inl4-week-old male and female bobwhite quail. Eight birds received I 0 mg/kg chlordane in the diet for l0 weeks; 20 quail were treated with l0 mglkg chlordane for l0 weeks followed immediately by l0 mg/kg endrin(987d in ttre diet; a fourth group of 20 birds received only 1 0 mg/kg endrinin the diet. The pesticides were dissolved in propylene glycol. After 9-l0 days on a control diet, survivors were sacrificed and their brainsdissected. No deaths occurred among the birds fed the control diet orl0mg/kg chlordane. With endrin alone, 15 birds died, and with thecombination 14 birds died. ln birds that received endrin alone, the residuelevels in thebrain were 0.34-1.84mg/kg in those that died and 0.28-O.62 mg/r;g in the survivors. ln the birds fed chlordane and endrin, theresidue levels wereO.IT-1.25 mg/kg in birds that died and 0.144.56 mg/kg in survivors. Birds treated with the combination had considerably morechlordane residues in their brains than did those fed chlordane alone. Themaln conclusion of this study was that the additive toxicity of closelyrelated chemicals should be taken into account in diagnosing cause ofdeath (Ludke, 1976).

7.2.5 Specialstudies

The influence of endrin at 5 and l0 mg/kg of feed on the activity ofvarious enzymes in the serum of juvenile cockerels was studied. Thegreatest increases in activity were measured for glutamate oxalacetatetransaminase, cholinesterase, and alkaline phosphatase. Smaller increaseswere observed for creatine kinase, glutamate dehydrogenase, c,-hydroxybutyrate dehydrogenase, and phosphohexose isomerase (Hom etal., 1987).

121

Effects on organisms in the environment

7.3.2.6 Behavioural studies

The effect of a sub-lethal dose of endrin (2 mgft;g diet) on avoidanceresponseswas studied in eight pens of 25 seven-day-old Cotumix quailchicks for 14 days. The stimulus used to elicit avoidance was a movingsilhouette, and the response was measured daily. Group avoidance responsewas significantly suppressed by exposure to endrin, but the behaviourretumed to norm al after 2 days on untreated diet (Kreit zer &Heinz, 197 4) .

Adult male bobwhite quall (Colinus virginianus) were fed a dietcontaining endrin at 0.1 or 1.0 mg/kg for 138 days (beginning ar 3 days ofage), and then their performance in five non-spatial discrimination reversaltasks was studied. Treated birds made 36-1 397o more efiors than conffols.and birds fed the lower dose made significantly more errors than thosegiven the higher dose after reversal 3 or 4 in the first three tests. The effectsof endrin were reversed after 50 days on untreated feed. The principaleffect of endrin was to impair the birds' ability to solve a novel problem.The mean levels of endrin residues in the brain were 0.075 mg/kg wetweight in those given the lower dose and 0.35 mg&g for those on rhe higherdose (Kreitzer, 1980).

7.3.3 Mammals

7.3.3.1 Toxicity

The LCro values for short-tailed male and female shrews (Btarinabrevicauda) aged 180, 105-150, and 30-75 dayswereS'l-I74 mg/kg dierfor 14 days (Blus, 1978).

Five groups each of 13-14 pairs of Saskatchewan deer mice(P ero myscus manbulatus) of various ages were fed endrin at 0, l, 2, 4, or7 mgkg of diet for intermittent periods, between which the animals wereeither fed a normal diet or were subjected to 48-h starvation. The animalswere sacrificed by exposing them to cold stress at -16 oC and the time ofdeath recorded. No influence was found on litter production, frequency, ormean litter size. At the higher levels of feeding, postnatal mortality beforeweaning was increased. Significant parental mortality occurred at 4 mg&gand higher and appeared to be dose-dependent (Morris, 1968). (Remark:Since the animals in this study were captured in the field and the periodsof feeding altemated with short periods of starvation in an effort to simulatepossible conditions in the field, this srudy is of only limited value).

122

I

3.3.2;I

EHC 130: Endrln

The effects of endrin at 8.0 azlacre (0'56 kglha) on unenclosed fieldpopulations of meadow voles (Microtus penrcylvanicas) and deer mice(Peromyscus maniculatw) were investigated in 1966{8. Animals weretrapped live on adacent 7-acre (2.8 ha) plots each summer at regularintervals, before and after a single application of endrin. Immediate,significant declines in the number of voles were seen on the experimentalplot, but no long-term toxicological effects were observed. The populationrapidly recovered, exceeding the initial ard control numbers in all threeyears. The experimental vole population thus appears to have respondedto endrin as it would to a local depopulation by trapping. The mousepopulation decreased significantly after the application of endrin in 1966and did not recover, and the highly unstable, transitory population on theexperimental plot indicated a long-term toxicological effect (Morris,1970,1972).

Studies of resistane

taC-Endrin in com oil was administered to a resistant and a susceptiblestrain of pine mi ce (M ic ro t us p ity mus p inc to rurn) orally at 0. 5 mg/lcg bodyweight, as follows: days l-5, unlabelled endrin; days 6-14,'aC-endrin;and day 15 unlabelled endrin. Total recovery of raC in both faeces and urinewwT6Vofor theresistant strainard53Vofor the susceptible strain. The twostrains produced the same major faecal and urine metabolite, but theresistant strain produced about twice the quantity as the susceptible strain.The quantitative differences in the excretion of more polar endrinmetabolites may indicate metabolic differences between the two strainsand, consequently, the greater tolerance of the resistant strain to toxiceffects (Peuella et al., 1975). The major metabolite was identified as cnJi-I 2-hydroxyendrin; one of the other more polar metabolites, found in minorquantities, was suggested to be a tertiary alcohol of endrin (Petrella et al.,1977).

The degree of toxicity of endrin in first-generation progeny ofsusceptible and resistant strains and a cross of the two strains of pine micewas studied by Webb et al. (1973). The LDro for offspring ofsusceptible x susceptible parentage was 5.0 mgikg body weight; that forresistant x resistant, 2 l. l mg&g; and that for suscep tible x resistant, 8.6 mglkg. These results offer preliminary support for a genetic mechanism withintermediate dominance. An increase in resistance against the toxic effectsof endrin was demonstrated in wild pine mice trapped in orchards whereendrin had been used for years. The oral LD, in susceptible mice was

12s

7.4

Ettects on organisms in the envlronment

about 3 mglkg body weight and that in resistant mice, an average o f 36 mg/kg body weight. The increased resisrance appeared to be heritable in thefirst generation (Webb & Horsfall, 1967; Webb et al., 1973). Althoughdifferences in the rate of metabolism of endrin could be demonsuated,especially in the activity of mixed-function oxidase, these did not appearto be sufficiently large to explain the resistance (Hartgrove et al., 197?).

Effects in the field

Episodes have been reported in which endrin was concluded to be thecause of death in fish and birds. Numerous fish kills were reported fromthe sugar-cane growing areas of Louisiana in 1960-63. No associationwith variables such as dissolved oxygen, pH, or temperature was found,but following the developmenr of sensitive analytical techniques it wasconcluded that the fish had been killed by endrin (Mount & t\tnicki,1966). Surfacerunofffromfields wasreported tobe the main sourceof theendrin that contaminated the rivers (Lauer et al., 1966), although effluentfrom an insecticide plant may have contributed since the fish containedtwo chemicals involved in endrin manufacture (Mounr & Putnicki, 1966).Levels of endrin found in studies of fish in the wild are siven in section5.1.4.2.

Declines in the population of brown pelicans in l-ouisiana wereattributed to endrin, although at least six other organochlorine pesticidesand polychlorinated biphenyls were found in rhe animals (Blus et al., 197 5 ;King et al., 1 977). The eggs of b'rown pel icans (P e I e c anus o c c ide nt al i s) inTexas, USA, wereexaminedfor endrinresiduesin 19?5*81. The compoundwas recovered only in 1975, in 15 of 18 eggs, ar levels of 0. l-O.3 mg/kg.In the same year, rhe highesr levels ofendrin were found in pelican eggsin Louisiana, and this maximum coincided with the dearhs of largenumbers of brown and white pelicans (P. erhyrorhyncos) (King et al.,1985).

Endrin was found in one of ten eggs of the American white pelican(Pelecanus erythrorhynchos) collecred in 1969, ar 0.20 mglkg, and in rwoof 35 samples collected in 1981, at up to 0.18 mg/kg wer weight. Brains ofpelicars founddead in the period 1975-81 had levels up to 0.80 mg/kg. Noendrin was found ineggs of the wesrem grebe (Aec hmop horus accidentalis)collected in 1981. It was concluded that endrin had caused some of thedeaths among pelicans in California (Boellstorff er al., 1985).

124

EHC 130: Endrln

The death of sandwich tems in The Netherlands was attributed to thedischarge of a combination of endrin and related pesticides into an estuaryfrom a manufacturing plant (Koeman et al., 1967,1969; Koeman, 1971).

On several occasions in Victoria, Australia, large numbers of wildbirds, in particular pigeons (Co lumba liv ia),sparrows (Passe r do rnes ticus)and Indian lnynahs (Gracula religiosa), were observed to be paralysed orin convulsions (Reece et al., 1985). The crops and livers contained endrinat levels of up to 1.2 mg/r.g.

Fulvous whistling ducks (Dendrocygna bicolor), which nest in ricefields along the south-eastem coast of Texas, USA, suffered a majordecline in population in the late 1960s, which was attributed to exposureto dieldrin or aldrin. Organochlorine pesticides were determined in 1983in the carcasses of 15 adult ducks immediately after their arrival in Texasfrom Mexico in the spring and before departure from Mexico in theauturrrr. Four of the ducks with high levels of dieldrin residues also hadresidues of endrin; and four other ducks, collectcd in 1 967 and 1969, hadendrin residues. The geometric mean levels in the diffcrent years werc0.03-0.08 mgkgwct weight; in juveniles in 19ffi-69, the geometric meanlevcl was 0. l6 mg/kg (Flickingcr et al., 1986).

The cffects of endrin on wildlife were studied in l98l-83 in fruitorchards in Washington, USA. A single application of endrin after harvestresulted in acute and chronic toxicity to a variety of avian species; mostdeaths occurred soon after the application, but scvcral raptors died duringthe spring and summcr. The brains of 73 of 125 birds contained endrin at<0.10--0.80mg/kg; detectable levcls occurred most irequently in thebrains of galliforms and falconiforms. The spccics in which the greatestnumbcrs o[ dcaths at"tributed to endrin occurrcd include California quail(Callipepta california), chukars (Alectoris chukar), and common barnowls ('l'yto albd). Of thc 97 eggs analysed, 68 contained detectable endrinresidues:51 had levcls of <0.10mg/kg, and the eggs of l0speciescontaincd 0.01-0.17 mg/kg wet weight (range, none detected to 1.67). Theauthors concludcd that cndrin was toxic to wildlife, although there was noevidence that it affectcd reproductive success or population level (Blus etal., 1989).

Levels found in birds in the wild are also given in section 5.1.4.1.

125

Effects on organisms in fhe envlronment

7.5 Appraisal of effects on organisms in the environment

Use of endrin in agriculture is the major source of its presence in theenvironment, but discharge of waste material from manufacturing andformulating plants has contributed to local contamination. World-widemonitoring surveys have shown that the concentrations of endrin in thebiosphere are generallyvery low (Table l0),bothabsolutely andrelatively:The levels of residues of other organochlorine compounds, particularlyDDE and polychlorinated biphenyls, are generally 100 times or higherrhan those of endrin.

Toxicologically significant levels of endrin residues have been fowrdlocally in fish and other organisms, particularly in cases in which endrinwas appliednearrivers and lakes and whenrunoff occurred into waterways.Residues may also occur when endrin is used as a seed dressing or in baitto control rodents.

The most serious adverse ecological effects that have been reportedwere the fish kills (and associated adverse effects on brown pelicanpopulations) in the Mississippi River system in the USA. Although theinitial evidence for ascribing theseeffects toendrin was circumstantial, theresults of analyses of dead fish were considered to confirm a causalrelationship; there is little doubt that endrin was a contributory factor in atleast some of these fish kills. The evidence that endrin was rhe primarycause of the decline in the brown pelican population is less convincing,since the harmful effects on reproductive success have been attributed toDDE and other factors (Blus et al., 1974, 1979).

In summary, agriculnual application of endrin should be such as toavoid or minimize contamination of waterways, either by overspraying orrunoff or by leaching from dressed seed in rice-growing areas. The effectsof the use of baits containing endrin for rodent control on non-targetorganisms should be assessed in the light of local circumstances. Finally,effluents from manufacturing and formulating plants must be treatedadequately before being discharged inro warerways.

126

l.t

8. EFFECTS ON EXPERIMENTAL ANIMALSAND

"V VITRO

The toxicology and risk assessment of endrin have been reviewed (USEPA, l987a,b; Anon., 1988a,b).

Acute toxicity of technical{rade endrin

Oral admlnlstration

Endrin ishigtrly toxic whengivenby the oral route and ismore acutelytoxic to mammals than its stereoisomer dieldrin (WHO, 1989), with anacuteoralLDroof 7.5-17.8 mg/kgbody weight (Iable 21), compared with50-60 mg/kg for dieldrin. There appears to be a sex-dependent sensitivityto the acute effects of endrin, female animals being more sensitive thanmales. A species-dependent sensitivity has also been reported, monkeysand cats being more susceptible than mice and rats.

Signs of intoxication may include increased initability and tremor,followed by tonic-clonic convulsions, ataxia, dyspnoea, gasping, andcyanosis. Convulsions usually occur 3Od) min after an oral dose, anddeath may occur within 24 h after the administration of a lethal dose (Speck& Maaske, 1958). Animals that survivepoisoning recover completely withno delayed or persistent effect.

Dermal administratlon

The acute dermal LD*s for technical endrin in various animal speciesare given in Table Z2.Endrin is highly toxic when apptied as a solution inhydrocarbon solvents but moderately toxic when applied as a dry powder.The signs of poisoning are similar to those seen after oral administration.

Pa renteral adm i nl stration

The acute LDros for technical-grade en&in given by parenteral routesof administration are shown inTable 23.

127

.2

.3

Etfects on experlmental anlmals and ln vltro

l < o o @ o @T @ c o N -

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Table 23. Parental LDrs for technical- grade endrin

Species Route Vehicle LD* (m9/k9 Referencebody weight)

Intraperitoneal Com oil 5.6

Intravenous Dimethylsulfoxide

lntravenous Ethanol

Graves & Bradley(1e65)

Walsh & Fink(1970,1972)

Hinshaw et al.(1e66)

2.3

Dog

l.ev.4.1

i

Toxieity of metabolites and lsomers

Mammalian metabolites

In a comparative study, the acute oral LD,os of endrin and three of itsmetabolites were determined in ras (Table Z). When the brairs of someof the rats were analysed for the presence of endrin and its metabolites, theconcentration of l2-ketoendrin in male rats given endrin at 60 mg/kg bodyweight was found to be higher (mean, 0.3 mglkg) than that of endrin(0.07 mglkg) 22h atter dosrng. In male rats intoxicated with syn-IZ-hydroxyendrin or l2-ketoendrin (at 16 mglkg body weight each), theconcentrations of l2-ketoendrin in the brain 30 min after dosing weremuch higher (mean values, I .9 and 1.4 mgkg, respectively) than those inthebrains ofrats given a similar butnon{oxic dose of antj- I 2-hydroxyendrin(mean,0.09 mg/(d and killed at the same time. The sigrs of intoxicationwere similar to those of endrin (Bedford et al., 1975b).

'Table 24. Acute oral toxicity of mammalian rnetabolites of endrin in rats

Compound Oral LD* (mg/kg body weight)

Female

95% Cl 95% Cl

Endrina nti- 1 2-Ay dr oxye ndri nsy*1Z-Hydroxyendrin12-Ketoendrin

5.62.41 .21 . 1

5.35.52.80.8

3.0-7.92.0-3.00.6-1.70.7-1.5

3.6-7.44.2-7.20.8-4.00.5-1.2

€5% Cl. 95% confidence interval

131

Effects on experlmental animals and in vltro

These results suggest that l2-ketoendrin may be the acute toxicant inrats. The production of l2-ketoendrin varies greatly from one mammalianspecies to another, however, andnonehas been detected in birds ofvariousspeeies thar were killed by endrin (Stickel et al., 1979).

8.1.4.2 Isomers

As described in section 4.2, endrin is changed under the influence ofsunlight into delta-ketoendrin. The acure toxicity of this isomer is given inTable 25. It is less toxic than endrin, and, like endrin, ir is more roxic rofemale than to male rats. The sigru of intoxication are similar to those seenwith endrin

The acute tocixity of ttreendrin aldehydehas beenreporred to be > 5@mgTkg body weight in male mice (Phillips et al., 1962).

Table 25. Acute toxicity of delta-ketoendrin

Sex and Routespecies

LDso (mg/kgbody weight)

Reference

Male rats OralFemale rats Oral

Male rats Oral

Rats Intravenous 5

Male rats Intraperitoneal 82

Mde mice Oral

Soto& Deichmann(1967)

Stanlord ResearchInstitute (1954)

Soto& Deichmann ( t967)

Stanford ResearchInsti tute (1953)

Stanford ResearchInstitute (1954)

Stanford ResearchInstitute (1953)

120-18010-36

62.1 (53.3-72.2)

23.6. (19.9-28.0)

Male mice Intraperitoneal 16.7

132

EHC 130: Endrln

1.5 Acute toxlcity ol formulated materlal

1.5.1 Oral and dermal administration

Oral and dermal LDro values for formulated endrin in rats (Muir, 1 970)are presented in Table 26.Dry formulations were administered orally asl-27o aqtte{)ns suspensions and dermally in both dry form and asz-SVoaqueous susperuions. In general, the typeof formulation did not signifi cantlyalter the acute oral toxicity of endrin. The dermal toxicity of tbe 507owettable powder was similar to that of the 207o emulsifiable concentrate;the27o field strength dwt was the least toxic.

Table 26. Oral and dermal LD*s for endrin lormulations in rats

Formulation LDro (mgd(g body weight)

Oral Dermal

Formulation Activematerial

Formulation Activematerial

20% Emulsifiable 20concentrate

50o/o Wettable 7.6powder

2hField streng$ 275dust

4,N

3.80

5.50

52.20 (undiluted) 10.90

21.80 (dry) 10.9014.40 (aqueousl 7.2O

5720 (dry) 114.401140 (aqueous) 2230

From Muir (1970)

Tenrabbits (body weight,2.44.1 kg) weretreated with anemulsifiableconcentrate containing 19.47o endrin on clipped skin at a dose of 200 mg/kg body weight, and the material was allowed to remain in contact with theskin for 24 h. Four of the l0 animals died within 48 h (Anderson et al.,1953). Two of 10 rabbits (body weight, 2.0-2.5 kg) neated similarly witha25Vo dust concentrate died within 48 h (Hine et al., 1954).

1.5.2 lnhalation

Ten adult rats were exposed for I h to a mist of of an emulsifiableconcentrate containing l9.4qo by weight of endrin in xylene, at a

133

8.2

8.2.1

8 .2 .1 .1

8.2.1.2 Rat

Eflects on experlmental anlmels and ln vltro

concentration of endrin slightly exceeding 2000 mg/m3 of air, and wereobservedfor48 h. The particle size of the mist and otherdetails of exposurewere not reported. Three of the animals died l-14 h afier exposure(Anderson et al., 1953).

Groups of l0 Long Evans rats were exposed for I h to 25Vo and3lVoendrin dust concentrates at a concentration of 2000 mg./m3 of air. Particlesize and other details of exposure were not provided, Five rats exposed tothe 307o and three exposed to the25%o dustdied within43 h afrerexposure(Iline et al.,1954).

Short-term exposure

Oral administration

Mouse

Feeding studies were conducted to estimate the maximum tolerateddoses of endrin in B6C3FI mice. Groups of five males and five femaleswere given a normal diet or one containing endrin at 2.5-20 mglkg for6 weeks, followed by observation for another 2 weeks. Three males andfour females given l0 mg/kg died, but no mortality occurred at 5 mgl<g.No data were provided on animals fed20 mgkg Hyperexcitability wasobserved in male mice given doses > 5 mgftg of diet. Mean body weightgains were comparable with those of controls. The maximum tolerateddose was calculated by exrrapolarion ro be 5 mg/kg of diet (NCI, 1978,1979).

Groups of three male and two to three female Carworth rats, either29 days or 6 months old, received daily doses of endrin at l, 2, or 5 mgkgbody weight inpeanutoilby gavage, on fivedaysper weekfor 6T-72 days.All rats given I mg/kg survived; the increased mortility in rhe orher groupswas dose-related: 2/5 females at 2 mgkg and 313 males ar 5 mgTkg daydied. Pathological findings ar auro?sy included diffuse degenerarivechanges in the liver, kidneys, and b'riin, while survivors showed no suchchanges. All treated animals lost weight and developed hypersensitiviry tostimuli (Treon et al., 1955).

134

EHC 130: Endrin

Groups of five male and five female adult Sprague-Dawley rats weregiven diets containing technical-grade endrin at 0, 1,5, 25,50, or lfi) mg/

kg diet over a maximal period of 16 weeks and were observed for

behaviour, weight gain, feed consumption, mortality rate, and symptoms

of toxicity. Alkaline phosphatase levels, determined once a week, were

higher in rats fed endrin than in the control group, and the total average feed

consumption of treated rats was less than that of the control group. All ratsfed 10O mg/kg of diet died during the first two weeks of the study, and only

twofemale rats fed 50 mg/kg of diet survived the experiment. All maleratsgiven 1 mg/kg and all female rats given 1 and 5 mg/kg of dier survived.Males appeared to be more susceptible than females to endrin in this study'The symptoms of intoxication were hypersensitivity to stimuli andconvulsions: hypersensitivity was noted in all rats, and convulsionsoccurred among rats receiving 25, 50, and 100 mglkg diet. Weight loss was

dose-dependent and significant in all rats treated with endrin (Nelson et al.,1956).

To estimate the maximum tolerated doses of endrin in Osbome-Mendel rats, groups of five males and five females were given diets withor without endrin for 6 weeks, followed by observation for another2 weels. Endrin was added to thediet in two-fold increasing concentrationsof 2.5-80 mg/kg. Mortality wasnot increased at l0 mg&g, and meanbodywcight gain wasnodifferentfromthatincontrols. At 20 mg/kgof diet, oneanimal of cach sex died. The maximum tolerated dose was calculated byextrapolation to bc 15 mg/kg diet (NCI, 1978, 1979).

2.1.3 Rabbit

Four of five female rabbits givcn an oral dose of endrin at I mg/kg

body weight on five days per week died following the administration of 2,

30, 35, and 50 doscs, respectively. Thc fifth rabbit survivcd 50 doses over

I a period of l0 weeks. Diffuse degencrative changcs wcrc obscrved in the

, liver and kidneys but not in the brain (Treon ct al., 1955).

2.1.4 Dog

Dogs (mainly two per group) fed endrin at 5-50 mg/kg of diet diedwithin 50 days. They regurgitated their food, became lethargic, salivated,and later relused to eat; they became emaciated and developed respiratorydistress and sigrs of stimulation of the central nervou.s system. Diffusedegenerative lesions in the brain, heart, liver, and kidneys, together with

135

Effects on experimental animals and ln vitro

pulmonary hyperaemia and oedema were observed. Three dogs fed dietscontaining 4mgkg of diet for 6months survived, but they showedreduced body weight gain and a slight increase in liver:body weight ratio;no histopathological change was observed. Ar 3 mg/kg of diet or less,growth was normal (Treon et al., 1955).

Beagles (one male and one female/group; control group, only onedog) were fed diets containing endrin at 0, l, or 3 mg/kg for 80 weeks. Nosign of intoxication was observed, and the weight gain of treated animalswas comparable to that of controls. The ratios of kidney and heart to bodyweight were increased ar 3 mg but nor ar I mg (about 0.(X5 mgikg bodyweight). No histopathological change was found in the viscera (Treon etal., 1955).

Groups of three male and three female pure-bred beagle dogs(4-6 months old) were fed endrin in the dier at 0,0.1,0.5, l, 2, or 4 mg/kgfor two years. Additional groups of four male and four female dogs werefed endrin at 0, 1, or 4 mg/kg of diet. Two males and two females of eachgroup were killed after 6 and I 2 months of feeding; no other death occurredduring the study. Convulsions were observed in three dogs at 4 mg and inone female at 2 mg; no other sign of intoxication or illness was apparenrduring the study. No adverseeffect was notedon growth, foodconsumption,haematology, orurinalysis, and no compound-related change was found inserum alkaline phosphatase, prorhrombin time, or any of the other clinicalchetnical parameters measured at regular intervals. All organ weights,relative as well as absolute, were normal, except for occasional, slightincreases in liver weight in some of the females at 2 and 4 mg in the diet.The only histopathological change found was a slight ro moderatevacuolation of livercells in dogs fed 2 and4 mg in the diet. Norenal changewas observed in any of the dogs (Jolley er al., 1969).

8.2.1.5 Domesticanimals

Sheep and cattle fed diets containing endrin ar 2.5 or 5 mgkg for112days showed no indicarion of harmful effects (details not given)(Radeleff, 1 956). The conwlsions and muscular tremors that were inducedin six I 0- I 8-month-old male buffalo calves administered a 207o emulsionofendrin led to a significant rise in lactic acid concentrarion in the bloodof the animals, possibly due to excessive production of the acid inside thefasciculating muscles (Verma et al., 1970).

136

EHC 130: Endrin

,2.2 Inhalatlan

'Three mice, three rats, two guinea-pigs, two hamsters, four rabbits,

and one cat were exposed to sublimed endrin vapour at an actual

concentration of 5.44 mg/m3for7 Wdayon5 days/weekforupto26 weeks'

Two rabbits died after 26 and 90 exposures, respectively, and one mouse

died after 22 exposures. No convulsions were observed, and all other

animals survived. Surviving rabbits showed a granulomatous type of

pneumonitis; no histological charrge was found in the other survivinganimals (Treon et a1., 1955).

Dermal administratlon

Three female rabbits with intact skin died after 19, 19, and 25

applications, respectively, of endrin as a dry powder at 150 rn/kg bodyweight for 2hlday on 5 days/week. Applications of 75 mg/kg resulted inthe death of one of three rabbits after 8 weeks; the other two survived for13-14 weeks-the end of exposwe. Convulsions, tremors, and twitchingof the facial muscles were the main signs of intoxication. Two of fiverabbits (dose not specified) showed severe fatty degeneration of the liver(Treon et al., 1955).

Skin irritation

Dry powdered endrin was applied repeatedly at a dose of 75 or150 mgTkg body weight for 2Vday,5 days/week for up to 14 weeks onintact or abraded skin of female rabbits (see section 8'2.3). No skinirritation was observed. Single applications of endrin as dry powder atdoses up to 250 mg/kg body weight for 24 h on rabbit skin causedno gross

or microscopic damage to the skin of the animals (Treon et al., 1955).

.2.3

l.+ Reproduction,embryotoxicity,andteratogenicityI

1.4.1 Reproduction

t.4.1.1 Mouse

CFW mice (20males and 20females) werefeddiets containing endrin(96Vo) at 0 and 5 mg/kg for 120 days, beginning 30 days before mating'

.3

t37

Etfects on experimental anlmals and ln vltro

Signifi cant parental mortality (32vo) andreduced litter size were observed,butfertility, fecundity, and the number of litters produced per pair were notaffected (Good & Ware, 1969).

8.4.1.2 Rat

Forty male and 80 female Long-Evans rats were fed endrin in the dietat 0, 0.1, l, or 3 mg/kg over three generations, each generation breedingonce. No difference in appearance, behaviour, body weight, or number orsize of litters was seen. The weights of the liver, kidneys, and brain werenormal, and no histopathological abnormality was seen in third-generationweanlings. The only significanr effect was increased mortality of pups inrhe second and third generarions of rars fed 3 mg/kg (Hine, 1965).

Ten male and 20 female Long-Evans rats were rreated similarly, buteach generation bred twice, weanling rats were mated after 79 days on thediets (when they were 100 days old). All pups from the firsr lirrers werediscarded at weaning, and the parent rats were mated again. Randomlyselected pups from the second litters were maintained on the diets andmated when 100 days old; this was done for three generations. Thenumberof pups in each lirter was counred on the day of birth and on the fifth day;on the twenty-first day, the weanlings were counted and weighed andeither sacrificed or saved for continuation. parent rats were weighed,sacrificed, and examined grossly when no longer needed. Ten male andl0 female F* weanlings each from the controls and the highesr dose-levelgroup and five males and five females from the 0. I and I .0 mg groups wereautopsied. Body, liver, kidney, and brain weights were recorded, andsections of these organs and from heart, lung, spleen, and testis werestudied histologically. Appearance, behaviour, body weight, number andsize of litters, organ weights, and histopathological appearance of F*weanlings were comparable wfth those in control animals. No effect onreproduction was observed in rats fed diets containing endrin at 2 mgkgover rhree generarions (Hine, 1968).

8.4.2 Embryotoxlcityandteratogeniclty

8.4.2.1 Mouse

Groups of l0CD-l miceweregiven a singleoral doseof endrin(99V")at 2.5 mg/kg body weight (stated ro be half the LDr) in corn oil by gavageon day 9 ofgestation; an untreated and a vehicle control group were also

138

EHC 130: Endrln

used. Fetuses wereexaminedonday 18. No significanteffect was observedon intrauterine death or fetal weight, but the incidence of total anomalieswas increased over that in controls: 2/1 l7 fetuses had cleft palates, threehad open eye, and two had other anomalies. No data on matemal toxicitywere reported (Ottolenghi etal., 1974).

These results could not be repeated by Kavlock et al. Female CD-lmice were given endrin (99Vo) at 0 (vehicle), 0.5, or 1.0 (groups of40 mice), or 1.5 or 2.0 mg/kg body weight (groups of 20 mice) in com oilby gavage on days 7-17 of gestation. The animals were killed on day 18.

Maternal deaths occurred in the 1.5 and 2 mglkg groups, reduced matemalweight gain was observed at and above I mg/kg, and matemal liver weightwas increased at 0.5 mgfkg and higher. Fetal weight and skeletal, andvisceral maturity were adversely affected at doses of I mglkg and above.No teratogenic effect or embryonic lethality was observed, even at dosesthat caused matemal death (Kavlock et al., 1981, 1987)'

In a study of the effecs of acute alterations in maternal health statusupon fetal development in the mouse, groups of 2l or 40 pregnant CD-lmice weregiven a single oral doseof technical-gradeendrin at0 (vehicle),7 or 9 mg/kg body weight in com oil on day 8 of gestation. The animalswere killed on day 18 of gestation. Three of 2l animals given 7 mg/kg(147o) and 19/40 mice gievn 9 mgkg (47Vo) died. Matemal weight gainwas decreased in both test groups; the total number of implantation sitesand number of viable litters were not affected, but fetal weight wasreduced. Delays in ossification ofthe skeleton and an increased incidenceof supemumary lumbar ribs were observed. Although three fetuses fromone litter in the 9 mg/kg group had fused ribs, no significant increase in theincidence of malformations was found. A statistically significant, linear,inverse relationship between matemal weight gain and the presence ofsupemumary ribs in their offspring was found (Kavlock et al., 1985)'

(.2.2 Rat

Five groups of 25 female CD rats were administered endrin (977o) inmethocel in oral doses of 0,0.1, 0.5, or 2 mg/kg body weight per day ondays 6-15 of gestation, or vitamin A, used as a positive control. Theanimals were killed on day 20. The largest dose of endrin caused matemaltoxicity, as evidenced by weight loss and mortality (two animals). Thefetuses showed some slight growth retardation (not significant) but noincrease in intrauterinedeath rate. No effect attributable to endrin was seen

139

Effects on experlmental animals and in vitro

on the mean number of viable fetuses, post-implantation losses,implantations, corpora lutea, fetal sex ratio, or fetal extemal, soft-tissue, orskeletal abnormalities. Bent ribs were observed in61522 fetuses treatedwith endrin, but not in relation to dose. An increase in delayed ossificationin slemebrae and skull of fetuses was seen in the treated groups incomparison with the untreated control group. Animals given vitamin A hada significantly increased number of post-implantation losses and malformedfetuses (Goldentahl, 1978a).

Groups of 32, 1 5, 28, 30, and 15 female CD rats were given oral dosesof endrin (997o) in com oil ar 0, 0.075, 0.15, 0.30, or 0.45 mg/kg bodyweight on days 7-2O of gesrarion. Rars were killed on day 21. Maternalweight gain was reduced at dose levels above 0. 15 mg/kg, bur no increasein maternal liver weight was found. Fetal mortality, weight, degree ofskeletal arrd visceral maturation, and incidences of skeletal and visceralanomalies showed no dose-relared effecr (Kavlock et al., l98l).

8.4.2.3 Hamster

Three groups of golden Syrian hamsters (7,24, and 8 animals/group)received a single oral dose of endrin (99Vo) in corn oil at 5 mgfkg bodyweight (stated ro be half the LD*) on day 7, 8, and 9 of gestation,respectively. Two control groups wereused, consisting of57 untreated and41 vehicle controls. The animals were killed on day 14. The number ofresorptions and ofdead fetuses was increased after treatment on days 7 or8 and to a lesser extent in the vehicle controls. The live fetuses in all threetreated groups showed significant growth retardation when compared withcontrols. The incidencc o[ anomalics was high only after rreatmcnt onday 8: congenital abnormalities werc secn in2\o/o of fetuses, withopen eyein22a/o, webbed footin l6%o,clefr palare in5Vo, andfuscd ribs inSVo.Theanomalies that appearcd to be increased significurtly but ro almost thesame extent at all three srages were fused ribs and cleft palate (ottolenghier al. , 1974).

These results could not bc repeate<i by other workers. Groups of27-29 golden Syrian hamsters were administered oral doses of endrin(97Vo)in methocel at 0 (rwo conrrol groups), 0. 1,0.75, or 2.5 mg/kg bodyweightondays 4-13 of gesration. Theanimals werekilledonday 14. Bodyweight gains of the animals given 2.5 mg/kg were slighrly reduced.Maternal appearancc, behaviour, and survival, mcan number of viablefctuscs, post-implantation losses, implantations, corpora lutea, fetal bodywcight, and crown-rump length showcd nochange attriburable to treatmenr.

140

EHC 130: Endrln

The number of malformations in fetuses was not increased, but ossifi cationof the stemeb'rae and certain ribs was delayed (Goldentahl, 1978b).

Groups of 18-87 golden Syrian hamsters (LVG strain) were givenendrin (987d as a solution in com oil by gavage either as a single dose of0.5, 1.5, 5,7.5, or l0mglkg body weight on day 8 of pregnancy or asmultiple dai ly doses of 0. 75, l. 5, 2. 5, or 3. 5 mglkg body weight on days 5-14 of pregnancy. All animals were killed on day 15. With single doses, noeffect was found on maternal survival, pregnancy rate, weight change orliver:body weight ratio, The only sign of matemal toxicity was theoccurrence of transient convulsions 2 h after dosing in one hamster givenl0 mg, No compound-related difference was noted in the number of

' implantation sites, fetal death rate, or fetal weight; indicators of skeletal, matwity were not affected. A dose-related increase in the incidence of

fused ribs was forurd in the groups given 7.5 and l0 mg/kg; increasedi incidences of meningo-encephaloceles were observed at 5 mg/kg andi above, with no dose-response relatiorship. No other compound-related

skeletal or visceral anomaly was noted. In the study of multiple doses,matemal toxicity (reduced weight gain and increased mortality) and fetaltoxicity (increasedmortality, reducedweight, reducedskeletal ossification,and an increased percentage ofirregular supra-occipitalis) were observedat doses of 1.5 mg/kg and higher. No treatrnent-related matemal or fetaleffect occurred at 0.75 mg/kg per day (Chemoff et al.,1979).

1.2.4 Perinatal behavioural development

Rats exposed perinatally to endrin at 0, 0.075, 0. I 5, or 0. 3 mg/kg bodyweight from gestation day 7 through day 15 of lactation showed nomortality andno influence on survival or growth. Pups of mothers exposedto 0.15 or 0.3 mg were more active than those of mothers exposed to0.075 mg or those in the control group. No clear difference in ambulationwas noted, and at90 days of age there was no difference (Grayet al., 1981;Kavlock et al., 1987).

Golden Syrian hamsters (LVG strain) given endrin (98Vo) ar 0 or1.5 mg/kg body weight per day by gastric intubation on days 5-14 ofgestation had a persistent increase in locomotor activity. Offspring oftreated hamsters ambulated more than the controls in the open field at15 days, and long-term observation of activity in the figure-8 mazeindicated that a significant increase in this behaviour was still present at125 days of age. Other behaviour pattems, including sexual, rearing and

1 4 1

8.4.3


rururing, and wheel behaviour, were unaffected. Dams repeatedly exposedto endrin at 0.75 and 1.5 mg/kg body weight were markedly hypoactiveunder the same testing conditions in which the pups were hyperactive. Thedose of l.5 mg/kg body weight killed more than half of the dams (Gray etal., 1981; Kavlock et al., 1987).

Appraisal ol reproductive effects

Endrin had no reproductive effecrs in three generations ofrats at alevel of 2 mg/kg of diet, equivalent to 0.1 mg/kg body weight. It had noteratogenic effect in mice, rats, or hamsters after oral exposure during theperiod of organogenesis. The significance of the anomalies observed inmice and hamsters by Ottolenghi et al. (1974) is uncertain. Studies in thesame strain of the same species using more rigorous protocols and largernumbers of animals could not confirm their findings,

The lowest-observed-adverse-effect level for maternal toxicity wasl.0mg/kg body weight in mice,0.3mg&g body weight in rars, and1.5 mg/kg body weight in hamsters. Embryotoxiciry was observed ardoses of I mg/kg body weight in mice and 1.5 mg/kg body weight inhamsters. The overall no-observed-adverse-effect levels in mice, rats, andhamsters were 0.5, 0.15, and O.7lmgkg body weight, respecrively(Table 27).

8.5 Mutagenicity and related end-points

8.5.1 Effects on microorganisms

Endrin was not mutagenic in numerous studies using Salmonellatyphimurium (TA98, TA100, TA1535, TA1537, TAl538, TA1950,TA1978, SL4525, 51,4700), Escherichia coli (WP2 uvrA,WPZ uvr , GalRs, WP2, hcr,p3478,W3100), K-12 (pol A,*/po\), wp67, cM6l l, andCM57L Bacillus subtilis {M45),Saccharomyces cerevisiae (D3, D7), andSerratia marcescens (a21, a742), with or without metabolic activation byrat or mouse liver 59 (Fahrig, 1974- Yan Dijck & van de Voorde, 1976;Ercegovich & Rashid, 1977; Simmon et al., 1977; Nishimura er al., 1982;Waters et al.,19821' Glan et al., 1983; Moriya et al., 1983; Rashid &Mumma,1986).

142

EHC 130: Endrin

143

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8.5.3

8.5.4

Effects on experlmental anlmals and ln vltro

No mutagenic effect was observed in S. typhirutrizrn strains TA98,TAl00, TA1535, orTA1537, with and without metabolic activarion with59 from livers of Aroclor 1254-induced rats and hamsters in the presenceof five concentrations of endrin (0-1 0 000 pg/plare) (7niger, 1987;Tnigeret al., 1987). No mutagenic effect was observed in S . ryphimurianr strainsTA97, TA98, TA100, or TA102 with and without metabolic activarionwith Aroclor 1254-induced rat liver microsome fraction in the presence ofseven concentrations of endrin(99.AVo), from I nglplate up to I mglplate(Mersch-Sundennann et al., 1988).

Point mutations in mammalian cells

Endrin was weakly mutagenic in 6-thioguanine-resistant mouseFM3Acells (Morita & Umeda, 1984; abstract only).

Domlnant lethal mutatlons

Endrin did not show detectable dominant lethality when given as asingle intraperitoneal dose (0.76 or 3.8 mg/kg body weight) or daily oraldoses (0.I or O.25 mglkg body weight) for 5 days to seven or nine maleICR/Ha Swiss mice, respectively. This study involved a sequenrial maringprocedure, in which one male was housed with three females for one week,repeated for 8 weeks (Epstein et al., 1972).

Chrom osomal and cytogenetic effects

Endrin at l0'5 and 10'4 M, but not at l06'produced a dose-relatedincrease in the percentage of Ml metaphases and a dose-related decreasein that of M3 metaphases at 48 h in treated LAZ-fi)7 human lympoid cells.This effect is closely related to the reducedrateofcell proliferation inducedby endrin (Sobti et al., 1983).

Intratesticular injection of 0.25 mg endrin in saline to three albino rarsdoubled the percentage of chromosomal changes in comparison with thatin the single control when rhe tesres were studied histologically l0 daysafter the injection. Changes were scored in 70-75 cells/animal @ikshith&Datta, 1973). The use of a single dose does not aid interpretation, and theincrease in chromosomal abnormalities may be related to cytotoxicityrather than to a genetic effect. The relevance of rhis type of study inmutagenicity testing is unknown.

144

EHC'130: Endrin

Chromosomalstudieswerecarriedoutonlymphocytesfromeightmale workers exposed to endrin and from six unexposed workers from the

same work area. No increase in the frequency of chromosomal abnormalities

was found, whether taken individually or collectively @ean, 1977)'

chromosomal aberrations were fourd in meiotic cells of barley and

somaric cells of barley and vicia faba grown from endrin-treated seeds

(Wuu & Grant, 1966' l967a,b). After treatment of root tips with 0'l7o

endrin(EC20solution)forl '5_2hatl0oC,thefunctionofthespindlewasdestroyed and did not interfere with the spreading of the chromosomes

duringsquashpreparation.Thecentromericregionbecamedistinctandvisible in prophase-metaphase chromosomes. At higher concentrations

, coirtraction, stickiness, and fragmentation of chromosomes were seen

(Bhowmik, 1978).

,5.5 Host-mediated effects

In two studies, male cFl mice were given single oral doses of endrin

in dimerhyl sulfoxide ar 3.75 or7.5 mgkgbody weight. control mice were

dosed with the solvent, and positive control groups were given a single oral

doseof ethylmethanesulfonate at400 mg&g body weight. saccharonryces

cerevisiae JDI suspensions were then injected intraperitoneally into each

mouse, and the suspensions of s. cerevisiae were harvested and analysed

after 5 h. No increase in mitotic gene conversion was detected (Brooks,

r976).

t.5.6 Sister chromatid exchange

Endrin ar conccntrations of 10'6-10{ mollitre in dimethyl sulfoxide

I (rt" latter dose was a cyrotoxic conccntration) failed to increase the

frequency of sisterchromatid exchangc significantly over the control value'

inratlivermicrosomal S9-activated and unactivatedincubationexperiments

1 using human lymphoid cells of the LAZ4W cell line (Sobti et al'' 1983)'

Il.S.l Etfects in Drosophila melanogaster

Endrin was not mutagcnic to Drosophila melanogaster after injection

at 0.2 plitre of a 0.001 o/o aqueous solurion, in the Muller-5 test for recessive

lcthal mutations on the X-chromosome (Benes & Sram, 1969).

145

Effects on experimentat animats and in vitro

8.5.8 Effeets on DNA

Endrin at l0-3 or 3 x l0-3 mol/itre did not induce mutarion in the adultratliverepithelialculture/hypoxanthineguaninephosphoribosyl transferaseassay (Williams, 1979).

DNA repair was not elicited in primary cultures of hepatocytes fromcD- I mice, Fischer 344 rats, or Syrian hamsters exposed to endrin for l g htogether with tritium-labelled thymine deoxyribonucleotide forincorporation during repair syrthesis. DNA repair was measuredautoradiographically. In rat and hamster liver cell cultures, a concentrationof 10-3 mol/itre and in mouse liver cell cultures, l0{ mol/itre endrin wastested (Maslansky & Williams, l98l).

Endrin did not induce unscheduled DNA synthesis in human hmgfibroblast cells with or without metabolic activation by rat livermicrosomel(five concentrations were tested, but they were not given in the paper)(Waters er al., 1982).

Endrin at eight concentrations ranging from 0.5 up to 1000 nmol/mldid not induce'nscheduled DNA synthesis in primaryrat heparocyres orin a modified Ames test utilizing concentration gradienf plates andl0 bacterial resrer strains (eight s. typhimuriwn and two E. colli lprobst etal., 1981)

8.5.9 Appraisal of mutagenlcity and related end-points

Garrett et al. (r986) evaruated the activity of endrin in a series of tests:for reverse mutation (point/gene mutations in prokaryotes), forwardmutation(point/genem,rarionsineukaryotes),differential loxicity (primaryDNA damage in prokaryotes), enhanced mitotic recombinaiion, geneconversion and crossing-over, urscheduled DNA synthesis (primary DNAdamage in eukaryotes), sisterchromatid exchange, chromosomal breakage,and dominant lethality (chromosomal effects). Endrin gave negativeresults in all these tests.

, The vast majority of the data indicate that endrin is not genotoxic;however, many of the studies would not reach current standards, or thevgive insufficient data to allow an independent assessment.

146

EHC 130: Endrin

t,l"l?11

Long-term exposure

Groups of 20 male and 20 female Carworth rats (28 days old) were

given dieti containing endrin at 0, 1, 5, 25, 50, or I 00 mg/kg' With I 00 mg'

iwomales and one female survivedfor 2 years; with 50 mg, four males but

no female swvived; and with 25 mg, 1l males and 5 females survived.

Survival at the lower concentrations was comparable to that of the control

group. Males appeared to be less susceptible than females to the toxic

actionofendrin. Signsof intoxication, hypersersitivity toextemal stimuli,

and occasional convulsions were observed only at the two highest levels.

The weight gain of females fed l, 5, ot 25 mgkgof diet was equal to or

greater than that of the control s after 40 weeks of feeding. In males fed

5 mg, growth retardation occurred during the first 20 weeks only, while

males that received 25 mg showed significant reduction in body weight

gain. The body weight gain of males fed 1 mg was comparable to that of

controls. The liver:body weight ratios were increased in males fed 5 mg or

more and in females fed diets with 25 mg or more' Histopathological

examination of animals that died during exposure to the three higher

dietary levels revealed diffuse degeneration of the liver, kidneys, brain,

andadrenal glands. Thefew survivors at50and 100 mg showeddegenerative

changes in the liver only. No histopathological change was fotmd in

surviving rats fed 1, 5, or 25 mgkg diet. There was no increase in the

incidence of neoplasia in the treated groups compared to the control group

Clreon et al., 1955).

This study indicates a no-effect level for endrin of I mg/kg of diet

(about 0.05 mg/kg body weight) but is inadequate in several respects, e'g',

survivalrate,detailsofpathology, andhaematological andclinical chemical.

data are not reported.

Carcinogenicity

Oral administration

Mouse

Groups of lfi) male and female C57B1/6J mice, an inbred strain with

a low incidenceof tumours, andC3D2F1/Jmice, ahybrid strain with ahigh

incidence of hepatomas in males and a high incidence of mammary

tumours in females, were fed endrin (997o) at dietary concentrations of 0'3

147

Effeets on experlmmtal anlmals and In vltro

or 3 mg/kg from the age of five weeks throughout life. A conrrol groupconsisted of 2(x) mice of each sex of each strain. Except for all groups o1female animals of the C3D2FI/J strain, this part of the experiment wasterminated at the 78th week because of the early occ'rr€nce of highnumbers of mammary fibroadenoma s in 7o-9ovo of control and treatedmice. Survival, growtlr, food intake, and haematology were not impaired.Mice of both strains fed 3 mg/kg diet occasionally developed convulsionsin the early stages offeeding but recovered and survived without signs ofillness. They generally showed the tlpical histological changes in the livercharacteristic of high doses of chlorinated hydrocarbon insecticides. Noeffect was observed on mice fed 0.3 mg/kg diet. The tumour incidence andtype of tumours were not influenced by the feeding of endrin, and it had noinfluence on the incidence of fib,roadenomas in female C3D2FI/J mice('tilitherup et al., 1970).

Groups of 50 B6c3Fl mice of each sex were given endrin in the dietfor 80 weeks and were then observed for a further l0 or I I weeks. Theinitial doses of endrin (97Eo) (z.s and 5 mglkg of diet) were poorlytolerated by males and were therefore reduced after 2s weeks to 1.2 and2.5 mgkg diet for males; bur females received 2.5 and 5 mglkg diet duringthe whole experiment, The time-weighted average doses were 1.6 and3.2 mgkgdier for males and 2.5 and 5.0 mglkg diet for females, Matchedcontrols consisted ofgroups of l0 mice ofeach sex; pooled controls, usedfor statistical evaluation, consisted of the matched control groups combinedwith 50 untreated male and 50 untreatedfemale micefrom simiiarbioassaysof other chemicals. All surviving mice were killed at 90 or 9l weeks. Meanbody weight was not affected, but the survival ofmales at thehighdose waslower than that of the controls. The survival of the low-dose males couldnotbeevaluated due to accidental administrationof excessivequantities ofendrin to this group during week 66. The tumour (neoplastic lesions in theliver) incidences in the high-dose males were higher than those of thepooled or matched controls, but not significantly so, and the increase wasnot considered to be related to the administration of endrin (Fredrickson,1978;NCI, 1978).

8.7.1.2 Rat

A study of groups of 20 male and 20female carworth rats administeredendrin ar 0, l, 5, 25, 50, ahO tOO mg/kg of dier was reviewed insection 8.6.1.1. Bearing in mind rhe limitations of this study, such as smallgroup sizes and low survival at the high doses, no evidence of an increase

148

EHC 130: Endrln

in the incidence of neoplasia was found in any of the groups (Treon et al',l9s5).

Groups of 50 weanlingOsbome-Mendelratsof each sex werefeddietscontaining endrin (987d at2,6,or 12mgkg for 29 months. The controlgroups consisted of I fi) males and 1 00 females. During the fi rst I 0 weeksof the study, only half the nominal dietary concentrations of endrin werefed. Sigrs of toxicity occurred in a few animals in all treatment groups,mainly in females, and included episodes of tremor and clonic convulsionswith 'outcries', the incidence of these signs being dose-related. Weightgain was unaffected, and the survival rates in control and treated rats weresimilar. The liver:body weight ratios were unaffected. A moderate (not

dose-related) increase in the incidence ofcentrilobular cloudy swelling inthe liver and of cloudy swelling of the renal tubular epithelium wasobserved. The lungs of the animals fed endrin exhibited a moderateincrease in the incidence of congestion and focal haemorrhages. Thetumour incidence in the treatment groups was comparable with that incontrol rats, and nodifference in the type of tumours was found (Deichmannet al., l970a,b; Deichmann & MacDonald,l97l).

In a life+ime study, groups of 24maleand?AfemaleOsbome-Mendelrats (22days old) were fed diets containing endrin at 0,0.1, 1,5, 10, or25 mgAg. Because 507o of the rats at?s mgkg died within the first week,this group was restarted with 32-day-old rats. Survival did not appear to beaffectedby treatrnent. The highest incidence of malignant tumours in maleand female rats occurred at 0.1 mglkg, but the malignancies were not dose-related. Treated male rats had a higher incidence of renal disease thancontrols, but this also was not dose-related (details not available) (Reuber,1978).

Groups of 50Osbome-Mendel rats of each sex were feden&in(97Vo)in their diet for 80 weeks and then observed for 3l or 34 weeks. Malesreceived doses of 2.5 or 5 mglkg diet; in females, the initial doses of 5 and10 mg/kg of diet were poorly tolerated and were reduced after 9 weeks to2.5 and 5 mg&g.The time-weighted average doses were 2.5 and 5.0 mg/kg for males and 3 and 6 mglkg for females. Matched controls consisted ofgroups of 10 rats ofeach sex; pooled controls used for statistical evaluationconsisted of the matched control groups combined with 40 untreated maleand 4.0 untreated female rats from similar bioassays of other chemicals. Allsurviving rats were killed at 100-114 weeks. Body weights and survivalwere not affected by administration of endrin. A slight increase in the

149

Etfects on experimental anlmals and in vltro

incidences of pituitary and thyroid tumours was observed, but no consistentstatistical significance or dose-response relationship was found(Fredrickson, 1978; NCI, 1978).

8.7.1.3 Tumourpromotion

No significant increase in the development ofpreneoplastic changes(hyperplastic nodules) was observed in rat liver after partial hepatectomyand initiation with N-nitrosodimethylamine or N-2-fl uorenylaceramide incombination with the administrarion of endrin (Ito et al., 1980).

In vitro, endrin at levels of above 2.5 pglml appeared to inhibitmetabolic cooperation in the hypoxanthineguanine phosphoribosyltrarisferase system using wild-type 6-thioguanine-sensitive V79 cells andvariant 6-thioguanine-resistant cells. Such inhibition is reported to be anindex ofpotential tumourpromoting activiry, although rhe test has notbeenvalidated (Kurata et al., 1982).

Endrin stimulated protein kinase C acrivity in vitro only slightly,whereas a reprcsental.ive endogenous ligand of protein kinase C, syn-|,2-didecanoylglycerol, srimulated protein kinase C ro a maximal velociry(Moser & Smarr, 1989).

8.7.2 Appraisalofcarcinogenlcity

One of several studies in mice suggests an increased incidence ofnonmalignanttumours in animalsof onc scx, butthis study was consideredinadequate for assessing carcinogenicity bccause an increascd number oftumours was secn in controls. A second study using a diflcrcnt mousestrain did not corroboratc the increase in tumour incidencc. Scveral long-term feeding studies in rats provide no evidence o[ a carcinogenic effect ofendrin. Its tumour promoting activity was Lested in vitro using proteinkinase C stimulation and ATPase inhibition; the resulrs do not suggest anyoverwhelming cffect in these systems. After a careful review of thisevidence, and taking into consideration the fact that most of the dataindicate that cndrin is not genotoxic, the Task Group concluded that rhedata are insufficient to indicate that endrin is a carcinogcnic hazard tohumans.

150

EHC 130: Endrln

B Specialstudies

9.1 Nervous system

9.1.1 Electrophysiological studies

The effects of endrin on bioelectrogenesis was studied in anaesthetizedpigeons and squirrel monkeys with chronically implanted electrodes'Endrin was administered intravenously topigeons at doses of 0.5-4 mg/kg

body weight. Doses of 24mgkg and higher caused seizure activity

throughout the telencephalon; the lower dose levels caused activity only

in the ectostriatum, a telecephalic visual projection area' At doses of

0.5-2 mg/kg body weight, endrin caused a specific increase in the evocationof potentials in the ectostriatum by stimulation of the nucleus rotundus, adiencephalic visual projection area. Reticular formation functions were

notorlittle affected. Administrationof endrin to squirrel monkeys atdosesof 0.2-3 mgikg body weight on 5 days/week intramuscularly in com oil

and saline emulsion induced characteristic changes in the electro-encephalogram (EEG), culminating in electrographic seizures; these were

transient and disappeared whenendrin administration was stopped. Seizuresreappeared under stress conditions, however, several months after endrintreatrnent (Revzin, 1966, 1980).

Groups of 20-60 Sprague-Dawley rats with previously implantedelectrodes were given endrin in peanut oil orally at 0.8, 1'7, or 3.5 mg/kgbody weight per day on 5 days/week for 28 weeks. Dose-dependentmortality occurred during the first week and again at the end of the study.Most changes in the EEG were seen after one week of exposure: theseincluded severe bursts of multiple spikes accompanied by clonicconwlsions; other animals had runs of spikes without full-fledgedconvulsions. The convulsions were usually preceded by a period ofhyperventilation After a further week of exposure, the rats showed normalEEG naces. Some irregular slow-wave activity was seen in animals thatwere moribund in the last month of feeding (Speck & Maaske, 1958).

The convulsive properties of endrin at l-2 mgkg body weight werestudied by intravenous injection in locally anaesthetized, paralyzed malecats, in which electrodes were placed in the subcortical structures of thebrain. Endrin was dissolved in ethanol (which itself stimulates or inhibitsthe central nervous system, depending on dose). Changes in the EEG andevoked responses were studied. Hypersynchrony, rhythmic bursts of

151


spikes and waves, and isolated spikes characteized the preictal state.Seizures were always bilateral and symmetrical and of a general tonic-ilonic type. Responses in sensory and motor cortexes to sensory nervestimulation were enhanced three to five fold. The authors concluded thatendrin is directly toxic to the mammalian nervous systern, is a potentrapidly acting conwlsant, and does not require metabolic activation to anactive metabolite (Joy, 1976).

8.8.1.2 Histopathological studies

Male CDl Swiss mice were administered endrin or sesame oil dailyby intraperitoneal injection in gradually increasing doses of l 5-4.0 mglkgfor 4-2O days. Electron microscopic examination of sciatic nerve tissuerevealed no morphological change in myelinated nerve fibres, myelin, orassociated Schwann cells, but morphological alterations were observed inunmyelinated nerve fibres and associated Schwarur cells: axons wereswollen, microtubules and neurofilaments showed dissolution, axoplasmwas replaced by large clear vesicles, vacuolization was present, andSchwann cells and adaxonal spaces also contained vesicles (Walker &Phillips, 1987; abstract only).

8.8.1.3 Neurotransmitter systems

gamma-Aminobutyric acid systez?,r: The role of the inhibitory neuro-transmitter of the central nervous system, gamma-aminobutyric acid(GABA),in the production of convulsions is well established. Polychloro-cycloalkane insecticides such as endrin have apotent excitatory actiononthe nervous system, and the interaction between GABA function andendrin has been studied.

Endrin srrongly inhibited GABA-dependent 3€l uptake by mousebrain vesicles, with an ICro (the concentration required to cause 507oinhibition) of 2.8 pmoffiitre. Inhibition was confined to that portion of 5Cluptake that is GABAdependent. The result demonstrates disruption ofGABA ionophore function in mammalian brain, possibly providing theprincipal mechanism of toxiciry (Bloomquist & Soderlund, 1985). In acomparison of the inhibitory potential of several polychlorocycloalkaneinsecticides on GABA-dependent 36Cl uptake, the most potent inhibirorwas l2-ketoendrin, followed by isobenzan, endrin, and then dieldrin,heptachlor epoxide, aldrin, heptaclrlor and lindane. This order closelyparallels their acute roxiciries (Bloomquist et al., 1986).

152

EHC 130: Endrln

The effect of these chemicals was also studied in the tert butylcyclo-phosphorothioate (TBPS) system, which has been shown to bindconvulsants with varying affinities. The IC* for endrin on 3sS-TBPS

binding wasO,22 pmofiitre and that for l2-ketoendrin,0.036 pmol/itre.These were the most potent inhibitors of TBPS binding, and there was asignificant linear correlation between 36Cl flux and TBPS binding(Bloomquist et al., 1986).

In vitro, endrin inhibited 3sS-TBPS binding in tissue from male Swiss-Webster mice with an ICro of 18 nmolfiitre (range, 4-90). In vdvo, dosesrepresenting 25,50, and lOMo of the LDro (8 mgftg intraperitoneally)inhibited 35S-TBPS binding with ICrs of 77 + 7 nmollitre (LDro) and39 + 6 nmol/lite(LD/2);noinhibition was obsewed atLDJ4, indicatinga possible no-observed-adverse-effect level. Brain P2 membranes oftreated mice contained endrin and l2-ketoendrin. The linding that thebrains of treated mice contained sufficient endrin or its biotrarsformedproducts to achieve TBPS binding and that this was correlated with theseverity of the poisoning indicates rhat the acute toxicity of endrin tomammals is regulated by GABA (Cole & Casida, 1986).

GABA-induced 36Cl flux into membrane microsacs was inhibited byendrin at 3.9 + 0.2 nmol/mg protein, which also suggests that endrininhibits the function of this receptor (Abalis et al., 1985, 1986). The ICrofor 5Cl influx was 0.19 10.06 pM and that for 35S-TBPS binding was0.ffi3 pM (Ganr et al., 1987).

Endrin inhibited both insect and rat GABA receprors in a dos e-related,non-competitive manner. It acts in a similar manner on the GABAreceptors in the central nervous system of the two species. The blockingaction may involvenon-competitivebinding to an allosteric site associatedwith the receptor's chloride channel (Wafford er al., 1989a).

Endrin potentially inhibits 35S-TBPS binding to rat brain membranesand also potentiates the protective effecr of NaCl (200 mM) against heatinactivation of 3H-flunitrazepam binding sites on the same membranes.The time courses of heat inactivation of these binding sires in the presenceof NaCl and saturating concentrations of endrin revealed monophasiccomponents constituting about 887o of the binding sites (Squires &Saederup, 1989).

t53

Effects on experlmental anlmals and in vltro

Endrin has also been shown to inhibit GABA-ergic function inTorpedo fish (Matsumoto et al., 1988), chicken embryros (Seifert, 1988,1989), themosquito fish (Gaarbusia ffinis) (Bonner & Yarbrough, 1989),and the cockroach (Periplaneta americana) (Wafford et al., 1989b).

Othcr amine system"s: Studies on the effects of orally administeredendrin on the content of biogenic amines in the brain of rats did notcontribute to an understanding of the convulsive action of endrin Oliller& Fink, 1973; Hrdina et al., 1974).

Cyclic AMP rnetabolism: Endrin did not affect adenylare cyclaseactivity or inhibit the activity levels of synaprosomal phosphodiesterase,enzymes involved in cyclic AMP metabolisrn, in rat brain. The authorsinterpreted their results to support their postulation that organochlorineinsecticidesexerttheirneurotoxic actionbyselectiveinhibitionof ATPasesin synaptosomes (Kodavanti et al., 1988).

AT P as e systems: Inhibition of ratbrain Na*-K'ATPase by chlorinatedinsecticides varied considerably: endrin and dieldrin were the least activein inhibiting both this enzyme and K*-srimulated para-nitrophenylphosphatase ataconcentrationof 2 x 10-5 mollitre. Results ofexperimentson ATPJ? exchange suggest that DDT is a powerful inhibitor ofoxidative phosphorylatiorl which may lead to depletion of ATP. Thiseffect was much less evident with endrin (Folmar, 1978).

Endrin caused about l5% inhibition of the acrivity of Na'-K-ATPasein rat brain synaptosomes at the highest concentration tested, 120 pM, andoligomycin-sensitive Mg2*-ATPase in rat brain synaptosomes wassignificantly inhibited in a concentration-dependent manner, to a maximalinhibition of 33Vo atthehighesr dose. Endrin did not inhibit oligornycin-insensitive Mgi*-ATPase, and it did not affect K*-stimulatd para-nitrophenyl phosphatase from rat brain synaptosomes; this enzymerepresents the dephosphorylation step of the overall reaction to theNa*-K'ATPase. Oligomycin-sensitive Mg2*-ATPase in beef heartmitochondria was significantly inhibited. The results of this study suggestthat the ATPase system in rat heart and central nervous system is notselectively inhibited by endrin (Mehrorra et al., 1989).

Sodium channel: It has been demonstrated using voltage clamptechniques in single cells that application of DDT prolongs the sodiumcrurent, which in tum decreases the depolarizing after-potential to initiate

154

EHC 130: Endrin

repetitive afterdischarges in the cell. The repetitive after-dischargesfacil i tate synaptic transmission and result in nervous systemhyperexcitability, which at the functional level is registered as tremors andeventually convulsiors and death (Narahasi, 1987). Even if less than l7oof the sodium charurels respond in this manner to insecticides, it issufficient to cause toxicity in the animal. Narahasi (1987) reported theseeffects with pyrethroids and a series of DDT analogues; such studies havenot been carried out with endrin. Lund & Narahasi (1983) suggested thatbecause of the similarity in the symptomatology of intoxication by thefamily of organochlorine insecticides, the target site of endrin may also bethe sodium channels.

?.r.n Appraisal of effects on the nervous system

The effect of endrin on the nervous system has received attentionbecause it has the well established ability to cause convulsions followingacute exposures. Endrin causes considerable changes in EEG activity,which are associated with convulsions, at intramuscular doses inexperimental animals as low as 0.2mgkg body weight.

The probable underlying mechanisms are associated with a dose-related, non-competitive inhibition of the GABA-ergic neurotransmittersystem. This is an inhibitory system, and removal of its action leads toincreased excitation in the nervous system. While inhibition of GABA-ergic function is common to anumberof polychlorocycloalkane insecticides,endrin, and particularly its metabolite l2-ketoendrin, have been shown tobe extremcly potent inhibitors of this function. It appears therefore that theacute toxicity of cndrin isdue to disruption o[GABA-relatedmechanisms.

Cardiovascular system

Studies have bccn conducted on the physiological effects ofendrin onthe peripheral vascular system, renal function, renal haemodynamics, andthe cardiovascular system of the dog (Emerson et al., 1963, 1964; Reins etal., 1964; Emerson, 1965; Emerson & Hinshaw, 1965; Reins et al., 1966;Hinshaw et al., 1966; Reddy et al., 1967). After a lethal doseof endrinwasadministered intravenously, most of the effects appeared to be the direct orindirect result of the stimulating action of endrin on the central nervoussystem. Bradycardia, hypertension, salivation, hyperexcitability, tonic-clonic convulsions, increased body temperature, leukocytosis,haemoconcentration, and decreased blood pH werc scen. Elevation of

155

8.2

Etfects on experimental anlmals and in vitro

cerebral venous pressure and cerebrospinal fluid pressure were alsoprominent features. Increased levels of adrenaline and noradrenaline inblood plasma cause increased venous retum and cardiac output andincreased arterial blood pressure in the absence of a rise in total peripheralresistance. There was a large increase in total limb vascular resistance andalso a decrease in renal blood flow due to arteriolar vasoconstriction. Instudies on intact dogs and isolated heart-lung preparations, high doses ofendrin appeared to have a toxic action on the left ventricle of the heart,causing sudden left heart failure.

Aldrin, dieldrin, and endrin inhibited rat brain synaptosomal andheart sarcoplasmic reticulum in vitro in a concentration-dependentmarmer.Calmodulin-depleted Ca2'pump activity was insensitive ro the action ofthese compounds. Oral administration of endrin at 0.5-10 mglkg to rarssimilarly decreased Ca2* pump activiry, in addition to decreasing the levelsof calmodulin in both brain and heart, indicating disruption of membraneCa2* transport mechanisms. Exogenous addition of calmodulin (l-20 pg)effectively reversed the endrin-induced inhibition. Ca2n pump activity inbrain is more sensitive to endrin than that in heart. The results indicate thatendrin may produce neurotoxic effects by altering calmodulin-regulatedcalcium-dependent events in neurons (Mehrotra et al., 1989).

9.8.3 Effects on liver enzymes

It is well known that chlorinated hydrocarbon insecticides such asDDT and dieldrin srimulare hepatic microsomal drug metabolism,stimulating the activity of enzymes for the metabolism of drugs andendogenous compounds such as hormones (Kinoshita & Kempf, 1970).

8.8.3.1 Mouse

A single oral, convulsive dose of endrin (20 mg/kg body weight)dissolved in corn oil was administered to 9-week-old male Swiss-Webstermice. Control groups consisted of a group of untreated mice and a groupreceiving com oil. When convulsions began, blood serum was examinedfor serum glutamic oxaloacetic transaminase, serum glutamic pyruvictransaminase, and serum lactic dehydrogenase. The activities of the threeelzymes were significantly increased above those seen in the two controlgroups (Luckens& Phelps, 1969).

156

iI8.3,2

EHC 130: Endrin

After intraperitoneal injection of a single dose of endrin at 6.25 mglkg body weight to mice, hexobarbital sleeping time was decreased, starting3 h after ttre idection and lasting for 3 days (Hart & Fouts, 1963).Stimulating effects on the hepatic mixed-function oxidase system werereportedin ICRmice aftersingleoral dosesof4 and l0 mglkg body weight(Hartgrove a al., 1977).

Rat

Feeding Sprague-Dawley rats on diets containing endrin at l, 5, ?5,50, or lfi) mg/kg for 16 weeks caused high mortality in all groups,especially among malerats. The serum alkaline phosphatase concentrationwas reported to be dose-relatedly increased in all groups as compared tocontrol animals. The effect was clearest in the groups fed 25 mg/kg of dietor more (Nelson et al., 1956).

In strain FW 49 rats, a single oral dose of endrin at 5 mg/kg bodyweight had no effect on pentobarbital sleeping time; l0 mg/kg caused asignificant reduction, which, however, disappeared after 1 0 days (Schwabe& Wendling, 1967).

Endrin caused a significant shortening ofthe duration oftheparalysisinduced by zoxazolamine in male Sprague-Dawley rats aged 5-6 weeks.Endrin was injected intraperitoneally at 2 mgtkg body weight daily for3 days, and zoxazolarrine was injected intraperitoneally on the fourth day(Truhaut et al.1974).

Male rats given single oral doses of 2.5, 3.15, or 5.0 mg/kg bodyweight showed no effect on the various parameters (details not given) ofmixed-function oxidase activity after 12 h, but the level of microsomalprotein and electron transport components per gram of liver weresignificantly increased after 108 h, in a dose-dependent fashion.Thiopentone and pentobarbital sleeping times were reduced by a 24-hprior intraperitoneal injection of endrin at 5 mgikg body weight (Kachole&Pawar,1977).

A single oral dose of endrin at 10 mg/kg body weight to male albinorats increased serum glutamic oxaloacetic transaminase and glutamicp5mrvic transaminase activities, and decreased ATPase, acid- and alkalinephosphatase, succinic dehydrogenase, and glucose-Gphosphataseactivitiessignificantly 248h after trea&nent (Meena et al., 1978). After three

157

Effects on experimental anlmals and ln vltro

successive daily oral doses of endrin at 15 mg&g body weight ro Sprague-Dawley rats, significant increases in total lipids and triglycerides in liverand in serum glutamic pyruvic transaminase activity were seen (Borady etal., 1983).

When two groups of six adult female rars were fed 0 or 28.7 ttgkgbody weight, endrin accumulated in the liver 647 mglkg),and itsconcentration in blood increased progressively up to 28 days. Growth wasdepressed, The activities of the enzymes aspartate amino transferase andalanine amino transferase were slightly increased (Illahi ct al., 1986).Similar results were obtained in a study in which rats were fcd 20 pg/kgbody weight for 28 days (Illahi et al., 1987).

8.8.3.3 Guinea-pig

Groups of six female guinea-pigs were administered three successiveintraperitoneal injections of endrin in sunflower oil at 3 mg/kg bodyweight, and liver and kidneys were studied Vl h after the last injecrion.Treatment caused a significant increase in liver weighr and a derrease inhepatic microsomal protein content; renal weight and renal microsomalproteincontent werenot affected. Hepatic cytochrome b5 and cytochrome-c reductase activities were increased, while cytochrome P450 and totalhaem levels were significantly decreased. Related to lhe decrease incytochrome P450 was a decrease in TPNH-linked aminopyrine-N-demethylatiorq but an increase in DPNHlinked demethylation was relatedto the increase in cytochrome b5 and cytochrome-c reductase. Lipidperoxidation was increased in both liver and kidneys (Pawar & Kachole,1978).

8.8.3.4 ln-vitrostudies

To test the possibility that phenobarbital induces cyrochrome P450pindirectly by increasing the availability of endogenous glucocorticoids inthe liver, phenobarbital and phenobarbitallike inducers, including endrin,were added to primary monolayer cultures of adult Sprague-Dawley rathepatocytes incubated in serum-free medium without glucocorticoids. De-novo synthesis ofcytochrome P450p, measured as increased incorporationof 3Hleucine into immunoprecipitable P45Op prorein, was increased.Endrin at a conce,lrtration of lxl0s M was half as potent as phenobarbitalat2x l&tM (Schuetz et al., 1986).

158

I

EHC 130: Endrln

Miscellaneous studies

Endrin inhibited rabbit muscle lactate dehydrogenase in vitro(Hendrickson & Bowden, 1976). Exposure of isolated rat enterocytes toendrin reduced the efficiency of the neuropeptide vasoactive intestinalp€ptide after stimulation of cyclic AMP accumulation, as was observedwith lindane (Carrero et al., 1989).

Endrin at single oral doses of 25 mg/kg body weight d'r daily dosesof I mg/kg body weight daily for 8 days induced various shifis in themobilization of the ions ofbiologically important metals such as magnesium,iron, zinc, and copper from liver, kidneys, brain, heart, spleen, and blood(Coleman et al., I 968 ; Lawrence et al., I 968). Rats receiving intaperitonealinjections of I mg/kg body weight in peanut oil over periods up to 19 daysshowed no alteration in the concentrations of serum proteins or senrmlipoproteins, separated by paper electrophoresis, or of albumin, alpha l,alpha 2, beta, or gamma globulins. Protein-bound sialic acid andmethylpentose were increased only temporarily; the levet of Lround hexoseincreased with time and that of bound hexosamine decreased (Coleman,1968).

Rats receiving a single oral dose of 50 mglkg body weight, dailyintraperitoneal doses of 2 mglkg body weight, or daily intramuscularinjections of 0.5 or 2.0 mgAg body weight for 45 days showed increasedactivity of a number of the enzymes that are involved in gluconeogenesisinlivercells andcells of therenal cortex. A significantdecrease wasnotedin hepatic glycogen, an increase in blood glucose and urea, as well as asignificant rise in hepatic and renal pyruvate carboxylase, phosphoenolpynrvate carboxykinase, fructose-1,6-diphosphatase, and glucose-6-phosphatase. Furthermore, endogenous levels of cyclic AMP were increased(Kacew etal.,1973: Singhal & Kacew, 1976).

Factors that influence toxlclty

Nutrition

The nuritional state of Wistarrats was found to altertheir susceptibilityto the acute toxic action of endrin. Three groups of approximately l(X) ratswere fed a normal diet, a diet containing casein as the onty source ofprotein, or a low protein diet for 28 days, and the acute toxicity ofendrinwas determined after a single intragasrric administration. The following

159

.5

Eftects on experimental anlmels and in vitro

LD, values were calculated:27 mg, 17 mg, and 7 mgkg body weight,respectively (Boyd & Stefec, 1969).

8.8.5.2 Potentiation

The acute oral LDrs of equitoxic doses of combinations of 10pesticides, including endrin, were studied in Swiss mice. No evidence ofpotentiation was seen with combinations with dieldrin, diazinon, malarhion,toxaphene, parathion, DDT, or dioxathion, bul more than additive effects,i.e., possible potentiation, were found with chlordane and possibly withaldrin (Keplinger & Deichmann, 1967).

Five groups of 20 male and 20 female Sprague-Dawley rars were fedfor9l days on a diet containing a combination of 15 'pcrsistent'chemicals

added at concentrations of 0, l, 10, 100, and 1000 rimes the water qualityobjective applicd in Canada. For endrin, these correspondcd to 0.fi)2,0.O2, O.2, and 2.0 Fglkg of diet. No effecr on food inrake, growth, clinicalchemistry, bone marrow, or histopathology were observed. It was concludedthat the presence of these chemicals at 1000 times the water qualityobjective had no toxicological effecr (Cote et al., 1985).

Six male and six female Sprague-Dawley rats were fed a control dietor diets containing endrin at 5 or l0 mglkg, endrin aldehyde at l0 mg/kg,orendrin ketone at 5 m&/kg for l5 days, at which time three to six rats fromeach treatment group were given a single intraperitoneal dose of carbontetrachloride at 100 plitre/kg body weighr in com oil (l mg/kg). Levels ofsenrm enzymcs, bile flow, and biliary excretion of an anionic modclcompound, phcnolphthalcin gluctuonide, weremeasured onday 16. Dicrarytreatmcnt with cndrin at cither dosc level did not elevatc scrum enzymelevels. Trcatmcnt with 5 mg/kg significanrly reduced bile flow and acorresponding rcduction in phenolphthalein glucuronidc excrction, w hereasthe l0 mg/kg dose reduced only phenolphrhalein glucuronidc eicrerion inmale rats. Fcmale rats treated with either dose showcd a dose-dependentcholeretic effect with a commensuratc increasc in phenotphthaleinglucuronide excretion. Treatment of rats with endrin and carbonteuachloride did not result in potentiation of hepatobiliary functions. Thelevels of somc scrurn enzymes were elevated (two-fold) in rats givenendrin plus carbon tctrachloride over those in rats given cndrin or carbontetrachloridc alone, indicating an additive interaction. Dictary trcatmentwith endrin aldchydc slightly increascd the lcvcls of scrum glutamicoxaloacctic transaminasc and glutamic pyruvic transaminasc; and endrin

160

EHC fiA: Endrin

ketone induced a small elevation in glutarnic pyruvic transaminase levels.Neither compound altered bilefl ow or biliary phenolphthalein glucuronideexcretion. Combination with carbon tetrachloride increased the levels ofsome serum enzymes (two-fold) over those seen with the aldehyde or theketone or carbon tetrachloride alone (Young & Mehendale, 1986).

9.1

9.1.1

9. EFFECTS ON HUMAN BEINGS

Exposure of the general population

Acute toxicity

In mildcases of poisoning, dizziness, weakness of the legs, abdominaldiscomfort, nausea, and vomiting have been reported. Some patients havecomplained of temporary deafness or were slightly disorientated oraggressive. Theonsetof poisoning isvariable andmayoccw 0.5-10 h afterconsumption of contaminated food or contamination of the skin; theinterval is usually 1-4 h, depending on the quantity ingested. Severepoisoning is manifested by sudden epileptiform fits, with frothing at themouth, facial congestion, and violent convulsive movements of the limbs,sometimes leading to dislocation of a shoulder or other injury. The fits maylasl for several minutes and may be followed by a period ofsemiconsciousness for 15-30 min or wrtil the next fit. In general, theseconvulsions occur suddenly, with no prodromal sign or symptom. Anuncommon but very serious symptom observed in two children washyperthermia (4 I oC orhigher); thehighfever was followedby decerebraterigidity. In fatal cases, death occurs within z-lzh.ln survivors, recoveryis rapid, within Z h, and uneventful, although some patients havecomplained of headache, dizziness, weakness, and anorexia for severalweeks (Davis & Lewis, 1956; Jacobziner & Raybin, 1959; Hoogendam etal., 19 62;Hayes, I 963 ; Weeks, 1 967; Hayes, I 982). After clinical recovery,EEG changes consisting ofbilateral synchronous theta-wave activity andoccasional bilateral synchronous spike and wave complexes, believed tobe associated with brain stem initation, may still be found and may persistfor up to several weeks (Hoogendam et al., 1962, 1965; Weeks, 1967).

9.1.2 Polsoning Incldents

Hayes (1982) reviewed poisoning cases caused by endrin. Outb'reaksof acute intoxication due to endrin have occurred by contamination of flourduring trarsport in railway cars. A first episode, which was well studied,occurred in 1956 in Wales, United Kingdom (Davis & Lewis, 1956): Atleast 59 people were ill enough to require medical treatmenr, and at least100 more had some symptoms, which were not severe enough to requiremedical advice. No one died. On the basis of the concentration of endrinin bread prepared from the fl ow ( I 50 mg/kg), Hayes ( I 963) esrimared that

162

EHC 130: Endrln

O.2C-n.25 mg/kg body weight may cause a single convulsion and that thedose necessary to produce repeated conwlsions is about I mg/kg bodyweight.Karplus(1971)estimatedthelethal dose inman tobeapproximately10 mglkg body weight.

A few conflicting data are available on the concentration ofendrin inthe tissues of victims of fatal intoxication. Hayes ( 1982) quoted levels of7-10 mg/kg in the liver and0.74.4 mg/kg in the brain; however, lO-foldlower levels were reported in the tissues of autopsied victims of anoutbreak of poisoning caused by ingestion of bread prepared fromcontaminated flour in the Middle East (Curley et al., 197O). ln anotherincident, two sacks of contaminated flour contained endrin at 184.5 and234.5 mgkg, and the bread androlls prepared from the contaminated flourcontained 125.67-176.ll mg/kg.The levels of endrin in serum, collected30 min, 20 h, and 30 h after convulsions in one person were 0.053, 0'038,and 0.021 mg/litre, respectively; three other cases had 0.003-O.0(X mg/litreof blood serum9-19 h afterconvulsions. Oneof these threepeople hadno symptoms (Coble et al., 1967). The reported serum or blood levels ofendrin associated with convulsions must be interpreted in the context ofthe rapid removal of endrin from blood and the often significant time lagin taking blood samples after convulsions. When the time betweenconvulsion and blood sampling islong, theendrin levelsreported are likelyto be much lower than those at the time of the convulsion.

Four outbreaks of endrin intoxication occurred in Doha (Qatar) andHofuf (Saudi Arabia) in 1 967, during which 874 people were hospitalizedof whom 26 die4 another5(X)--750 people showed symptoms of intoxicationbutrequirednohospitalization. Theseoutbreaks weredue to contaminationof flour by endrin leaking from drums during shipment, The endrinconcentrations found in bread were48-1807 mg/kg, and those in the bloodof patients were 0.007-O.032 mg/litre (Weeks, 1 967; Curley et al., 1 970).

Between July and September 1984, an epidemic of endrin poisoningoccurred in Pakistan, resulting in acute convulsions. In I 8 of 21 affectedvillages surveyed, 70Eo (1061152) ofthe cases for which age was knownwere in children aged l-9 years;9.8Vo (l9ll94) of the affected peopledied. A composite sugar sample taken from the houses of three casescontainedendrin at0.04 mg/kg. Endrin was ddtected in the bloodof 12118patients, at levels of 0.3-254.0 pgllitre of serum. It was also determinedinbrain, kidneys, adipose tissue, and liverofoneperson and found at levelsof 1680, 1760, 4010, 1430 ytgtLg respectively (Anon., 1984; Hill et al.,1986; Rowley et al., 1987).

163

Effects on human bings

In mid-March 1988, three members of a family in Orange County,Califomia, USA, became ill within I h of eating taquitos (baked corn shellfilled with spicy meat and salad). Two of the three had multiple giand malseizures. Subsequently, two other people were reported to have hadseizures less than 12 h after eating taquitos. All fivepatients had obtainedthe taquitos from the same shop within 5 days. The food was analysed, andthe presence of endrin was confirmed but not quantified. The origin of theendrin could not be identified (Anon., 1989).

An episode of acute endrin poisoning was reported in 33 Mexicanchildren, who had sudden seizures without sensory alterations (Singh &West, 1985).

Several other cases have been published of single accidental orintentional intoxications, in children and in adults (Jacobziner & Raybin,1959; Karplus, I 97 I ). Reddy et al. ( I 966) described 60 cases offatal endrinpoisoning out of95 encountered in India after the introduction ofendrin inagricultural work as an insecticide in 1959. The majority of the cases weresuicidal. Froth;petechial haemorrhages, a kerosene-like smell and massivepulmonary oedema were the characteristic autopsy findings. Respiratoryfailure was the most common cause of death. The authors concluded thatthe toxic dose of endrin is 5-50 mgTkg body weight or about I g; the lethaldose is about 6 g. In a poisoning case in a l9-year-old male who ingestedan trnknown amount of endrin, conwlsions and gross pulmonary oedemawere found (Jedeikin er al.,1979). No histological changes were found inthe liver. At least some of the pulmonary changes seen in such cases maybe due to aspiration of the petroleum hydrocarbon solvent in formulationsof endrin.

A case of polyneuropathy of the Guillain-Barr6 type was attributed toexposure to a mixture of DDT and endrin. Since convulsions were notrecorded, the causal relationship remains doubtful (Jenkins & Toole,'954).

In a fatal case of endrin poisoning, ingestion of I 2 g of endrin by a 49-year-old man caused convulsions (persisting for 4 days), hypersalivation,hyperthermia, renal insufficiency, thrombocytopenia, and recurrenthypotension. Death followed after I I days due to pulmonary complications(infection and haemorrhage) and hypoxaemia causing bradycardia andcardiac arrest. The endrin concentrations in blood 4 h and 6 and 1 I daysafter ingestion were 450, 86 and 7 1 pgllitre. Endrin levels in adipose tissue,

164

2

?.1

EHC 130: Endrin

heart, brain, kidneys, and liver, ll days after ingestion were 89.5, 0.87,0.89, 0.55, and 1.32 mg/kg, respectively (Runhaar et al., 1985).

The medical treatment of endrin poisoning is described in Annex II.

Occupational exposure

Factory workers

No fatal casc has becn reportcd due to occupational exposure inmanufacturing and formulating plants (Van Raalte, 1965; Jager, 1970),which may be due in part to underreporting but is also certainly due to thefact that occupational exposure involving the absorption of lethal dosesoccurs rarely under practical circumstances. Furthcrmore, the rapidmetabolism of endrin minimizes build-up of toxic levels in tissues duringnormal working days.

Several cascsof acute,non-fatalpoisoning occurred in amanufacturingplant in The Nethsrlands due to accidental over-exposure to endrin (Jager,1970). Endrin had bccn manufactured in this plant since 1957. During thefirst 9 ycars of pr<xluction of aldrin, dicldrin, and cndrin in the plant,l7 cases ol'poisoning with convulsions crccurrcd, fivc of which involvedmore than one convulsion. Threc 0[ thc cascs were due to acute over-cxposure to cndrin among workers who werc handling thcse materials athigh concentrations cvcry day. Thcre was no fatality during 1300 man-years of exposurc. No evidence was ftrund of skin sensitization, and therewas no case of permanent, partial, or complete incapacity. No differencewas seen in absenteeism due to illncss among these workers in comparisonwith those in othcr plants, and the results of liver function tests andcomplete blood cell counts were within normal limits. In the cases ofpoisoning, recovery from clinical and ncurological signs, including EEGtracings, was rapid and complete (Hoogendam et al., 1962, 1965; Jager,1970; Vcrstceg & Jager, 1973).

A scrics of studics has bcen published on thc rcsults of continuingmcdical supcrvision o[ workers in this plant . A complementary follow-upol' I 89 workcrs and of 52 workers who had left employment at the plant forvarious reasons was published in 1973 (Versteeg & Jager, 1973). Theseworkers had becn exposed to endrin for up to 14.5 years in 1973. In

165

Effects on human beings

agre€ment with data published from a study of 7l workers in an endrinmanufacturing plant in the USA (Hayes & Curley, 1968), endrin was notfound in the blood of these workers, except in cases of accidental, acuteover-exposure. Medical supervision of workers employed in themanufacture andformulation of endrin andotherpesticides for l-19 years(average, l2years), data on absenteeism, the results of tests for liverfunction and blood chemistry, blood morphology, urine analysis, theoccurrence of sensitization, the pattern and cowse of EEG changes in casesof poisoning, other medical studies (including electrocardiography, chestx rays, blood pressure, body weight), and the incidence and pattem ofdiseases, including the occurrence of malignant growths, showed nodifference between workers exposed to endrin and other chemical plantoperators. Residues of endrin were not found in plasma (< 3 pgllitre) or inadipose tissue (< 0.03 mg/kg).

A significantdifference was foundbetween workers exposedto aldrinand dieldrin only, workers not exposed to insecticides, and workersexposed to endrin only: endrin workers had lower blood levels of the DDTmetabolitepcra,para'-DDE than the other workers, and the levels werelower than those in the general population of the surrounding area,althoughDDT andrelated compounds hadneverbeen manufactured in theplant. A second parameter that was compared was excretion of 6-beta-hydrocortisol in the urine. (Increased activity of the drug-metabolizingenzyme system increases the activity of the oxidative pathway by which6-beta-hydroxylase converts endogenous cortisol to 6-beta-hydrocortisoland thus, relatively, diminishes the contribution of the reductivepathway,leading to excretion of 17-hydroxycorticosteroids.) Theratio of theurinaryexcretion of 6-beta-hydroxycortisol to that of l7-hydroxysteroids wassignificantly higher in the endrin workers than in workers not exposed toendrin (Jager, 1970).

A third parameter of this enzyme system that was studied was urinaryexcretion of D-glucaric acid (an end-product of the glucuronic acidpathway in the liver), which has been shown to increase after exposure tomicrosomal enzyme-stimulating compounds, like endrin (Hunter et al.,I 97 I ; Notten & Henderson, I 975). In the endrin workers, urinary excretionof D-glucaric acid after a week ofexposure increased significantly overpre-exposure levels and those in a control g,roup of workers. Excretiondiminished again after 3 days without exposure (Hunter et al., 1972;Ottevanger &Van Sittert, 1979; Vrij-Standhardt et al., 1979; Van Siuerr,r985).

166

,2.2

EHC 130: Endrin

Since anti-L}-hydroxyendrin is the only metabolite found in the urineof endrin-exposed workers, a study was initiated to find whether there is

a conelation between the quantity of this metabolite and that of D-glucaricacid excreted in the urine. A positive relationship was found betweenexcretion of the endrin metabolite and of D-glucaric acid after 7 days'After exposure w as discontinued, excretion of ant i - l2-hydroxyendrindecreased faster than that ofD-glucaric acid. The fact that endrin-exposedworkers hadD-glucaric acid levels within the normal range after 6 weeksindicates that enzyme induction in endrin workers is reversible. Theauthors concluded that a urinary level of anti-|z-hydtoxyendrin of0.130 pglg of creatinine is the threshold exposure level, below whichenzyme induction is not produced (Ottevanger & Van Sittert, 1979; VanSittert, i985). Endrin did not increase total urinary porphyrin excretionover that in a control group of employees (Strik, 1979; Nagelsmit et al',1979; Vrij-Standhardt et al., 1979).

In a follow-up mortality study of the same group of workers, vitalstatus and cause of death were assessed for 232 of a group of more than1000 workers. This group was selected because they had experiencedhighexposures in the initial years of manufacture and formulation and becauseof the long periods of exposure (mean, 11 years; rmge, 4-21) andobservation (me aq M years; range, 4-29). Total observed mortality was25, whereas 38 deaths were expected on the basis of mortality statistics forthe male Dutch population. Of the nine cancer deaths, three were due tolung cancer; the remaining six were due to cancers of stomach, pancreas,bladder, and kidney, multiple myeloma, and cerebral glioma. It wasconcluded that the pesticides manufactured had no specific carcinogenicactivity (Ribbens, 1985).

Dose-respo nse relatio nshi ps

It has not been possible to establish a dose-response relationshipbetween single or repeated oral exposwes and endrin concentrations inblood, adipose tissue, or organs and severity of intoxication, because theactual oral intake in the accidental cases was not knowq and the onset ofsymptoms of intoxication and the time of measuring concentrations ofendrin in blood, organs, or tissues were not comparable (Davis & Lewis,1956; Hayes, 1963; Coble et al., 1967; Weeks, 1967; Curley et al., L970;Karplus, 1971; Hayes, 1982; Anon., 1984).

167

9.2.3

Effects on human beings

Blood samples have been analysed in ttuee cases of acute over-exposure (Table 28): A formulator and an operator were accidentallysplashed with a 207o endrin emulsifiable conqentrare, which was washedoff within 10 min. Neither developed signs or symptoms of intoxication.The third case was in a formulator who handled technical-grade endrinpowder without wearing a dust-mask. He had convulsions 4 h after startingwork, but after treatrnentrecoveredfully the nextday. Blood samples fromfour colleagues working next to him, but wearing dust-masks, were alsoexamined. The author estimated that the threshold level of endrin in theblood below which no sign or symprom of intoxication occurs is50-100 Fgtitre and that the halflife of endrin in blood is in the order ofAh(Jager,1970).

Exposures to mixtures

A retrospective mortality study was carried out on workers employedin the manufacture of heptachlor and endrin in a plant in Tennessee, USA,between 1952 and 1976. The study comprised 835 men who had workedfor more than 3 months up to 20 years at the plant. No overall excess ofdeaths from cancer was found; however, there was an excess of deathsfrom cerebrovascular disease (7 obsirved, 2.3 expected) (Wang &MacMahon, 1979).

A further retrospective cohort study was conducled to examine themortality of workers employed in the manufacture of chlordane, heptachlor,DDT, aldrin/dieldrin, and endrin in a plant in Colorado, USA, whereendrin was manufactured from 1953 until 1965. Approximarely2100 workers who had been employed for at leasr 6 monrhs in the plantswere involved. No excess of cereb'rovasculardisease was observed @iuagliaet al., l98l).

Neitherstudy proves conclusively thatexposwe to these organochlorineinsecticides is associated with increased prevalenceof malignancy orothercause of death, but rhey are limited in design and in the desciption of

'

exposure.

A field study was carried our in 1983 in the Ivory Coasr ro assess rhehealth hazards associated with the handling and application by hand-heldsprayers of an ultra-low volume formulation consisting of endrin at 85 glitre, DDT at 333 gllitre, and merhylpararhion at 85 g/litre in petroleumsolvent. Groups of five or six farmers sprayed 3 litreTha of the formularion

168

EHC 130: Endrln

Table 28. Concentrations of endrin in blood from acutely over-exposed workers

Case Time of firstsampling

Endrin concentration (pg/litre)

Fi rs t 12h 24h 36hsample later later later

5 dayslater

Formulator

Operator

Formulatorwithout dusl-mask

Four colleagueswith dust-masks

t h after 90accident

40 min after 27 25accident

Directlyafter 80conwlsion

Same t ime ND-l0time as above

ND

ND20

ND

ND, not detectable (< 5 pg/litre)

4-6 weeks after sowing cotton and again l5 or 30 days after the firstapplication. The spray apparatus was filled and cleaned by the same men.The recommended protective clothing was wom only rarely, and thehandling and application techniques werecareless, resulting in many casesin appreciable skin contamination. No adverse health effect was observed.Absorption of endrin was monitored by measuring the concentration ofanti-|2-hydroxyendrin in spot samples of urine collectcd about 20 h afterspraying. The mean concentrations after the first, second, and thirdapplications were 0.34 (range, 0.04-0.59), 0.52 (range, 0.09-1.4), and0.45 mglg of creatinine (range, 0.(H).92). One person who had handledand sprayed the formulation carefully still had anti-|2-hydroxyendrin inthe urine after the third application, but at a very low level (0.03 mg/g ofcreatinine). Measurements of para-nitrophenol, a metabolite of methyl-parathion, inurine indicated that therate of metabolism of methylparathionwas increased as a result of enzyme induction by endrin in the liver(Kummer & Van Siuert, 1984, 1986). It was concluded that endrinaccumulated in most of the farmers after three applications within a shortperiod. An increase to toxiq levels might result if spraying were morefrequent and at shorter intervals and if the recommended clothing was notwom.

169

Effects on human tuings

9.2.4 Appraisal of effects of occupational exposures

Endrin is a very toxic compound. Several episodes offatal andnon-fatal poisoning have occurred, mostly from accidental contamination offood and also from intentional (suicidal) ingestion. The lethal oral dose isestimated to be l0 mg/kg body weight. In non-fatal cases, recovery is rapidand complete within a few days. The oral dose that causes a singleconvulsion is esrimated to be 0.25 mg/kg body weight, and that whichinduces repeated convulsions, 1.0 mg/kg body weight.

Exposure ofworkers to endrin for long periods did not induce adverseeffects that were attributed to this compound, although occasional cases ofacute, non-fatal intoxicationdue to accidental over-exposurehave occurred.Endrin was not detected in the blood of workers exposed to endrin at< 3.0 pgflitre. The threshold level of endrin in blood rhat resulrs inintoxication is esrimated ro be 50-100 tlElli:re. Absorption of a roxic doseis therefore unlikely during crccupational cxposure if recommendcd controlsand precautions are uscd. In fatal cases, endrin conccntral.ions in blood ashigh as 450 pgllitre have been reporred; however, it is not possible toestablish a dosc-response relationship. Since endrin is not normally foundin air, warer, or food, except under conditions of contamination, exposureof the general population is not significant.

170

10. PREVIOUS EVALUATIONS BY INTERNATIONALBODIES

Endrin was evaluated by the Joint FAO/TVHO Expert Committee on

Pesticide Residues in 1963, 1965, and 1970 (FAO VHO,196/',1965,1971). h 1970, the Committee established an acceptable daily intake(ADI) for humans of 0-O.CX[2 mg/kg body weight, which was based on

thelevel thatcausesno toxicological effectinrats anddogs, 1 mg/kg ofdiet(equivalent to 0.05 mg/kg body weight per day in rats and 0'025 mgikg

body weight per day in dogs).

The Joint FAO/$/HO Codex Alimentarius Commissionhas published

maximum residue limits for endrin (table}9; (FAOAilHO' 1986b).

Table 29. Codex maximum limits for the sum of residues ofrdrin and delta-ketoendrin

Commodity Maximum residue limit(mg/kg product)

Apples

BarleyCottonseedCottonseed oil (crude)Cottonseed oil (edible)Eggs (without shells)Meat (carcass fat)

MirkPoultry (carcass tat)Rice (husked or polished)

Sorghum

Sweet maize

Wheat

lAt or near the limit of detectiontxtraneous residue limit

The International Agency for Research on Cancer (IARC) concludedin 1974 and 1987 that there was inadequateevidence for thecarcinogenicityof endrin in experimental animals and that the evidence from studies in

humans was inadequate. Endrin was therefore classified in Group 3: not

classifiable as to its carcinogenicity to humans (IARC, 1974, 1987).

o.o2ao.o2a0 .10 .10.0240.2o .1bo.ooo8b10.024o.o2ao.o2'o.o2a

171

Prevlous evaluatlons by lnternational bodles

kr 1988, the Pesticide Developmenr and Safe Use Unit, Division ofVector Biology and Control, WHO, classified technical-grade endrin ashighly hazardous in normal use (WHO, 1992). A data sheet on endrin wasissued in 1978 (WHO/FAO, 1975).

REFERENCES

Abalis lM, Eldefrawi ME, & Eldefrawi AT (1985) High-affinity stereospecific binding ofcyclodiene insecticides and thexachlorocyclohexane to faminobutyric acid receptors ofrat brain. Pestic Biochem Physiol, 24: 95-102.

Abalis lM, Eldefrawi ME, & Eldefrawi AT (1986) Effects of insecticides on GABA-inducedchloride influx into rat brain microsacs. J Toxicol Environ Health, 18: l3-23.

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EHC 130: Endrin

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EHC 130: Endrin

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EHC 130: Endrin

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EHC 130: Endrin

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Wuu KD & Grant WF (1967b) Chromosomal aberrations induced in somatic cells of Vrbrbfababy pesticides. Nucleus, 10(1): 37-46.

Yakushiii T, Watanabe l, Kuwabara K, Yoshida S, Hori S, Fukushima S, Kashimpto T,Koyama K, & Kunita N (1979) Levels of organochlorine pesticides and polychlorinatedbiphenyls (PCBs) in mothers milk collected in Osaka prefecture from 1969-1976. ArchEnviron Contam Toxicol, S: 59-66.

Yarbrough JD, Roush RT, Bonner JC, & Wise DA (1986) Monogenic inheritance ofcycfodiene insecticide resistance in mosquitofish, Gambusia affinis. Experientia (Basel),42:851-€53.

Young RA& Mehendale HM ( 1986) Effectof endrin andendrin derivativeson hepatobiliaryfunction and carbontetrachloride-induced hepatotoxicity in male and female rats. FoodChem Toxicol, 24(8): 853-868.

Zabik MJ, Schuetz RD, Burton WL, & Pape BE (1971) Photochemistry of bioactivecompounds, Studies of a major photolytic product of endrin. J Agric Food Chem, 19(2):308-313.

Zavon MR, Hine CH, & Parker KD (1965) Chlorinated hydrocarbon insecticides in humanbody fat in the United States. J Am Med Assoc, 193(10): 181-183.

Zeiger E (1987) Carcinogenicity of mutagens: predictive capability ot tte Salmonellamutagenesis assay for rodent carcinogenicity. Cancer Res, 47: 1287-1296.

Zeiger E, Anderson B, Haworth S, LawlorT, Mortelmans K, & Speck W (19871 Salmonellamutagenicity tests: lll. Results from the testing of 255 chemicals. Environ Mutagen, 9(supp l9) :1 -110.

Zimmerli B & Marek B (1973) [The pesticide load ol the Swiss population.l Mitt GebLebensmittel Hyg,,64(4): 459479 (in @rman with English summary).

2 1 7

ANNEX I

CHEMICAL NAMES OF ENDRIN AND ITSMETABOLITES

Two main systems are crurently used for the nomenclature ofcyclodiene insecticides:'polyhydroaromatic' names, used by ChemicalAbstracts (American Chemical Society) and the Intemational Union forPure and Applied Chemistry (IUPAC), and the von Baeyer[UPAC systemfor polycyclic aliphatic compounds. Benson (1969) and Bedford (1974)proposed that the latter system be used for the cyclodiene insecticides.

The'polyaromatic' systemhas, unfortunately, been subject tohistoricalvariation, and there are differences between the IUPAC, British andAmerican conventions for defining the three-dimensional stereochemistryin this system. As a consequence of differences in the numbering of carbonatoms in the two systems and the modification of the Chemical Abstracts'polyaromatic' name for dieldrin since 1971, considerable confusion canarise in the nomenclature of metabolites. The possible misunderstandingsthat may occur, particularly among people who are not familiar with thevarious conventions of chemical nomenclature, are illustrated by thedifferent names that are given to the major metabolite of endrin; this onecompound may be designated as:

antl9 -hydroxyendrin (former Chemical Abstracrs system)anti-8-hydroxyendrin (current Chemical Abstracts system)anti-|2-hy &oxyendrin (von Baeyer/[UPAC system).

A useful discussion of nomenclature was given by Brooks (1974).

The chemical names for endrin and its metabolites are summarized inTable 30.

218

EHC 130: Endrln

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ANNEX II :

MEDICAL TREATMENT OF ENDRIN POISONING

Symptoms of polsoning

Endrin is readily absorbed and is toxic when taken by mouth, by skincontact (especially liquid formulations), and by inhalation. It stimulatesthe central nervous systern, and an oral dose of0.25 mglkg body weightsan cause convulsions in humans. Following accidental ingestion or grossover-exposure, symptoms appear between 20min and l2h and mayincludeheadache, dizziness, nausea, vomiting, weakness in the legs, andconvulsions, sometimes leading to death.

Organochlorine compounds c:ur cause respiratory depression, andthey may sensitize the heart to endogenous catecholamines, leading toventricular fib'rillation and cardiac arest in severe cases. Respiratorydepression may lead to metabolic acidosis, and if necessary blood gasesshould be checked. Use of an elecrocardiographic monitor is recommendedif symptoms are severe.

Endrin is eliminated very quickly from the blood and can be detectedfor only I or 2days even after massive over-exposures. Signs andsymptoms of poisoning occur only at levels in whole blood of above0.05 pglml.

Medical treatment

Medical treatrnent is largely symptomatic and supportive and isdirected against convulsions and hypoxia. If endrin is swallowed, thestomach should be emptied as soon as possible by careful gastric lavage(with a cuffedendotracheal tube already inplace), avoiding aspirationintothe lungs. In a rural situation where this is not feasible, vomiting should beinduced immediately. This should be followed by (intragastric)administration of 50 g of activated charcoal and 30 g of magnesium orsodium sulfate in a 3AVo aqueous solution. Oily purgatives arecontraindicated, and no fats,.oils, or milk should be given.

221

Annex ll

If conwlsions occur, anticonvulsants should be given immediatelybut slowly, and repeated as necessary. Diazepam can be given at 10 mg(children, I -5 mg) intrave, rously; thiopental sodium or hexobarbital sodiumcan be give,n intravenously at a dose of 10 mg/kg, with a maximum totaldose of up to 750 mg for an adult; or paraldehyde can be given at 5 ml byintramuscular injection. These short-acting anticonvulsants should alwaysbe followed by phenobarbital given orally at 3 mg&g (up to 200 mg for anadult), or phenobarbital sodium given intramuscularly at 3 mg/kg (up to2A0mg for an adult).

Morphine and its derlvatives, adrenaline and noradrenaline,should neverbe given.

The airway must be kept unobstructed. Respiratory inadequacy,which may be accen&ated by barbinrrate anticonvulsants, should becorrected, and oxygen and/or artificial ventilation may be needed.

A guideline for the management of major status epilepticus is addedas Annex III.

222

ANNEX III

MANAGEMENT OF MAJOR STATUS EPILEPTICUSIN'ADULTS"

Inltlal management

1. Assess the patient, verify the diagrrosis, remove false teeth, place thepatient in a lateral semi-prone position, and establish an airway.

2. Give diazepam intravenously (see Note l, below), usually at l0 mg in2 ml (0.154.25 mgk$, followed immediately by a further l0 mg(2 ml) over l-2 min. This may be repeated according to response.

3. Take blood to me$ure levels of anticonvulsant drug, ethanol, andblood sugar (5 ml of blood in a sugar tube); a sample to measurecalcium (5 ml in a plain tube); and a drop of blood ro determine bloodglucose.

4. If the latter measurement shows low blood glucose level, 25 ml of507o glucose should be given intravenously, preferably by catheterand not into a small distal vein. If ethanol is likely to be present, givethiamine intravenously at 100 mg.

5. Give phenytoin intravenously ar 250 mg in 5 ml (10-15 mg/kg) nofaster than 50 mg (l ml)/min by infusion pump or slow inrravenousinjection (see Note 2, below).

lf fits continue, transfer patient to the intensive careunit and consult an anaesthetist

6. Givechlormethiazoleintravenirusly at 8 mg/ml: a loadingdoseof upto 800mg (lffiml) over l0min at lOml/min, maintained with0.5-1 ml/min (4-8 mg).

%,ff,GE- guidelines issued at Guy's Hospital, London

223

7.

8.

Annex lll

Give thiopentone intravenously at 5 mglkg as a loading dose, then1-3 mglkg per h to a maximum blood level of 100 mg,/litre.

If this fails, consult a neurologist.

Notes

l Diazepam: A bolus injection of l0 mg may causerespiratory depressionand hypotension, which may be pronounced if there is concurrent useof other central nervous system depressant drugs, especiallyphenobarbital.

Diazepam must no, be given intramuscularly:-added to an intravenous infusion-with phenobarbital, unless artificial ventilation is available.

Rectal administration of diazepam (using a rectal administration set),at 5 or l0 mg in 2.5 ml, may be used for the immediate treatment ofepilepsy instead of intravenous diazepam.

2. Phenytoin must no, be given:-intramuscularly-by central line-into a dextrose infusion-with any other drug.

Intravenously administered phenytoin should be monitored bycontinuous electrocardiographic recording. If this is not available, itmay be safer to use a diluted solution of 250 mg (5 ml) in 250 ml ofnormal saline, no faster than 50 mg/min. The diluted solution shouldbe used immediately provided there is no evidence of precipitation(this use of phenytoin is not licensed).

Options

, The following drugs may also be used:

l. Paraldehyde: 2 x5 nrl by separate deep intramuscular injection orl0 ml diluted in lfi) nrl of normal saline given inrravenously over10-15 min. Note: Paraldehyde should be administered only withglass syringes.

224

3.

4.

2.

3.

EHC 130: Endrin

Phenobarbital: 200 mg/rnl, should not be given intravenously exceptwhen artificial ventilation is available, and not at all if the patientnormally takesphenobarbital. Themaximal rate of infusion is l0O mg/min to a maximum dose of 15 mg/kg.

Lignocaine: 100 mg by slow intravenous injection, followed by50-100mg in 250m1 of 57o dextrose at l-2mglmin. Note: Thistreatment must be monitored by electrocardigram.

4. Diazepam: l0 mg in 2 ml intravenously, or 40 mg in 5fi) ml of 57odextrose at a maximal infusion rate of 100 mg/h.

5. Sodiumvalproate:4O0 mg in4 ml, or400-8(X) mg intravenously over3-5 min (up to l0 mg/kg), followed by intravenous. infusion to amaximum of 2.5 glday (unlicensed).

Paediatric doses

For children, dosing should be adapted as follows:

Diazepam:Phenytoin:Chlormethiazole:

0.24.3 mg/kg intravenouslyI G-20 mg/kg intravenously5-10 mg/kg per h, equivalent to0.6-1.25 ml/kg per h

225

RESUME ET EVALUATION; CONCLUSIONS;RECOMMANDATIONS

R6sum6 et 6valuatlon

Expositlon

L'endrine est un insecticide onganochlor6 utilis6 depuis les anndes1950 contre toute sorte de ravageurs, qui s'attaquent notatnment au cotonmais 6galement au riz, i la canne d sucre, au mar's et ir d'autres cultures, Onl'utilise 6galement comme rodenticide et avicide. Il est disponible dans lecornmerce sous forme de poudres, de granul6s, de pites et de concentr6s6mulsionnables.

L'en&ine pdndtre principalement dans l'atmosphEre par volatilisationet dispersion. En g6n6ral, la volatilisation se produit aprds dpandage sur lesol et sur les r6coltes et elle est tributaire de nombreux facteurs comme lateneur en matidres organiques et en eau du sol, l'humidit6, les courantsadriens et I'aire foliaire des v6gdtaux.

C'est principalement par lessivage i partir du sol que se produit lacontamination des eaux superficielles. Les pr6cipitations, qu'il s'agisse deneige ou de pluie, n'ont qu'une partn{gligeable dans cette contamination.

Localement, une contamination peut 6galement se produire par suitedu d6versement d'effluents industriels ou de n6gligences dars les techniquesd'6pandage.

C'est principalement par suite d'un dpandage direct sur lesterrains et les recoltes que I'endrine p6nbtre dans le sol. Elle peut y €treretenue, transport6e ou d6grad6e, en fonction d'un certain nombre defacteurs. C'est dans les sols riches en matidres organiques que la rdtentionest la plus importante. La persistance de I'endrine d6pend dans une largemeslue des conditions locales; sa demi-vie dans le sol peut aller jusqu'i12 ans. La disparition de I'endrine pr6sente en surface s'effectueprincipalement par volatilisation et photoddcomposition. Sous I'influencedelalumidresolaire (rayonnement ultra-violet),I'endrine est isomdris6e endelta-c6toendrine. En pr6sence de lumidre solaire intense, on a observd uneisom6risation de 507o de I'endrine en l'espace de sept jours. L'isomdrisationpeut 6galement s'effectuer par action microbierure (champignons etbact6ries), notanunent en ana6robiose.

226

EHC 130: Endrin

Les invert6br6s aquatiques et les poissons absorbent rapidementl'endrinepr6sentedans l'eau mais, transvas6s dans une eau non contamin6e,les poissons expos6s 6liminent sans d6lai le pesticide. En cas d'expositioncontinue, le facteur de bioconcentration peut atteindre l4-18 000'

Il est possible que les invert6br6s terricoles absorbent facilementI'endrine. La pr6sence occasionnelle de faibles quantit6s d'endrine dansI'air ainsi que dans les eaux de surface, notarnment destin6es d laconsornmation, enzone agricole, n'a gudre d importance aupoint de vuedela sant6 publique. La seule voie d'exposition importante est la voiealimentaire. En g6n6ral, toutefois, les quantit6s ingdrdes se situent trdslargement en-dessous de la dose journalidre admissible qui a 6t6 fix6e d0,0002 mg&g de poids corporel en 1970 (FAO/OMS, l97l).

Absorption, m6tabolisme et excr6tion

Contrairement i la dieldrine, son st6r6oisomdre, I'endrineestrapidementm6tabolis6e par I'organisme animal et, comparativement i d'autres composdsde structure chimique semblable, elle s'accumule trds peu dans les tissusadipeux.

L'absorption et I'excretion sont rapides aprds administration orale ides rats et la demi-vie biologique se situe entre I et 6 jours selon 1esquantit6s ing6rees. Un r6gime stationnaire, c'est d dire un 6tat d'6quilibreentrela quantit6excr6t6eet la dose ing6ree, s'dtablit au bout de 6 jours. Onconstate rure diff6rence entre les deux sexes en ce sens que les mdlesexcrdtent l'endrine et ses m6tabolites par la voie biliaire plus rapidementque les femelles, d'oi une moindre accumulation de pesticides dans lestissus adipeux des mdles. Les rats excrdtent ce compos6 principalementdans leurs matidres f6cales sous forme d'endrine,d' anti-t2-hydroxyendrineainsi que sous la forme d'un ddriv6 hydroxyl6 de I'endrine, en I'espace deZ heures (70- 757o); un troisibme m6tabolite,la l2-c4toendrine, s'accumuledans les tissus. Les lapins excrdtent 5OVo des m6tabolites de I'endrine parla voie urinaire, l'excr6tion urinaire n'6tant qre de 2V" chez le rat; dans lesmatidres fecales des lapins, on ne retrouve que de l'endrine non modifi6e.

Des vaches i qui l'on avait administr6 de I'endrine i raison de 0,1 mg/kg de nourriture pendant 2l jours en ont excr6t6jusqu'ir 657o sous formede mdtabolites urinaires, 2OVo sous forme de m6tabolites f6caux oud'endrine non modifrf,e et3Vo dans leur lait, cette fois, principalement sous

227

1.3

B6sumd

forme d'endrine non modifide. Chez ces vaches, les rdsidus atteignaient0,003-0,006 mgflitre dans le lait, 0,001-O,002 mglkg dans la viande, et0,02-0,1 mg/kg dans la graisse.

Chez des poules pondeuses ayant regu tule alimentation additionn6ed'endrine, on a observ6 des r€sidus (selon la dose ing6rde) qui atteignaient0,1 mg/kg dans la chair, I mg/kg dans la graisse, 0,24,3 mg/kg dans leseufs Qawre), 0,Zmgkgdans les reins et 0,5 mg/kg dans le foie.Sauf dansle cas du foie et des reins, les r6sidus prdsents 6taient essentiellementformds dendrine non modifi6e. Environ 507o de la quantit6 d'endrineadrninisrCe a 6td excrdtde dans les maderes f6cales, principalement sousla forme de mdtabolites.

Clrez l'homme, le rat, le lapin, la vache et la poule, le principalmetabolite de I'endrine est I'anti-12-hy&oxyendrine, accompagn6e de sesSulfo- et glucuro-conjugu6s. On trouve 6galement 4 autres m6tabolites,mais en quantites minimes. Dans les tissus et le lait on retrouveessentiellement de I'endrinenonmodifi ee. Aprds 6pandage str des v6g6taux,on a retrouvd de I'endrine sous forme non modifiee ainsi que deux produitsde transformation hydrophiles.

Effets sur les 6tres vavants dans leur milieu naturel

L'endrine n'exerce que des effets minimes sur les bact6ries et leschampignons te.rricoles. Aux doses de I 0- I 000 mg/kg de terre, le composdn'a aucun effet sur la d6composition des matidres organiques, sur lad6nitrification ou sur la production de m6thane. L'endrine est trds toxiquepour les poissons, les invert6br6s aquatiques et le phytoplancton; la CLroir 96 h, est dans la plupart des cas inf6rieure d 1,0 pgflitre. La dose nociveld plus faible observde au cours d'un test portant sur le cycle 6volutif d'uncrevette, Mysidopsis bahia,6tait de 30 ng/litre.

Les 6preuves detoxicitd aigud effectudes sur des organismes aquatiquesont 6t6 pratiqudes dans des aquariums ne comportant pas de s6diments; onpeut penser que la pr6sence de sddiments attdnue I'effet de I'endrine.D'ailleurs la pr6sence de s6diments fortement contamin6s n'a gudre eud'effet sur les espdces de pleine eau, ce qui incite I penser que I'endrinefix6e aux sddiments pr6sente une faible biodisponibilit6. On n'a paspratique d'6preuves sur des animaux aquatiques vivant dans les s6diments.

228

EHC 130: Endrln

Pour les mammiferes t€NTestres et les oiseaux, la DLro est de l'ordre de1,0-10,0 mglkg de poids corporel. Des canards de I'espdce Anasplatyrlrynchos qui avaient regu pendant 12 semaines de I'endrine dans leurnourriture i des doses allant jusqu'i 3,0 mg/kg de poids corporel, n'ontpr6sent6 aucun effet d6l6tlre que ce soit sur la ponte, la f6condit6 oul'6closion des ceufs.

Il sembleraitquecertaines especes d'invert6br6s aquatiques, depoissonset de petits mammifdres r€sistent e I'action toxique de I'endrine; d'ailleursI'exposition ir diven pesticides organochlords a pu entrainer la sdlection desouches r6sistantes i I'endrine.

Dans des zones oi existent des decharges industrielles et of I'endrinepeut ere entrain6e par ruissellement i partir des champs trait6s, on aobserv6 une mortalit6 parmi les poissons; par ailleurs, le ddclin despopulatiors de p€licans bruns (en Louisiane) et de caugeks (aux Pays-Bas)a 6t6 attribuee ir une exposition i l'endrine et i d'autres d6riv6s halog6n6s.

Effets sur les anlmaux d'exp6rience et sur les systemes in vitro

L'endrine est un pesticide fortement toxique dont les signesd'intoxication sont de typeneurologiques. Chez les animaux de laboratoire,la DLro par voie orale de l'endrine de qualit6 technique se situe dans lesimites de 3-43 mgikg de poids corporel; la DLro dermique va de 5-20 mg/kg de poids corporel pour le rat. Il n'y a pas de diffdrence notable concemantla toxicit6 aigud par voie orale et percutande entre le produit technique etles diverses formulations (concentr6s dmulsionnables ou poudresmouillables).

Des 6preuves de courte durde portant sur la toxicit6 par voie orale del'endrine ont 6td effectu6es sur des souris, des rats, des lapins, des chienset autres animaux domestiques. Chez les souris et les rats, les dosesmaximales toldrdes ont 6t6 respectivement de 5 et l5 mg/kg de nourriturependant 6 semaines (soit l'6quivalent de 0,7 mg/kg de poids corporel). Lesrats ont survecus i une dose de I mg^cg de nourriture pendant 16 semaines(soit I'equivalent de 0,05 mg/kg de poids corporel); les lapins sont mortsaprds avoir regu d plusieurs reprises une dose de I mg/kg de poids corporel.chez le chien, une dose de 1 mg/kg de nourriture (soit approximativemenr0,025 mg/kg de poids corporel) administree sur une pdriode de 2 ans, n'aproduit aucun effet.

229

R6sumd

Du point de vue neurologique, les signes d'intoxication observ6s sontdus d I'inhibition de la fonction de I'acide gamma-aminobutyrique (GABA)i faible dose. Comme les autres hydrocarbures chlor6s insecticides,I'endrine agit 6galement au niveau du foie et la stimulation des systBmesenzymatiques intervenant dans le metabolisme des autres substanceschimiques se manifeste, notanrment chez la souris, par une diminution dela dur6e du sommeil induit par l'hexobarbital.

Des doses de 75-150 mg&g appliqu6es sur 1'6piderme des lapins sousforme de poudre slche, tous les jours pendant deux heures ont entrain€ desconvulsions et lamortchez ces animaux sars toutefois provoquerd'irritationcutan6e. Cette intoxication par voie g€n6rale sarx irritation locale m6rited'6tre signalee.

Des 6tudes de toxicit6 et de canc6rog6nicit€ d long terme ont 6t6effectudes sur des souris et des rats. Aucun effet canc6rogdne n'a 6t6observ6 mais ces 6tudes pr6sentaient trrr certain nombre d'insuffisancesnotamment la faible survie des animaux. Lors d'une 6tude de deux ans surdes rats traites par de l'endrine administree dans leurnourriture, on a estim6n I mg/kg de nourriture, soit l'dquivalent d'environ 0,05 mgtkg de poidscorporel, la dose sans effets toxiques observables. Aprbs administrationd'endrine avec des quantit6 infinit6simales de substances chimiquescanc€rogdnes pour I'animal, il na pas 6t6 possible de mettre en 6videnced'effet tumoro-promoteur. Le Groupe de travail en a conclu que lesdonn6es sont insuffisantes pour permettre de consid6rer l'endrine corunecanc6rogdne pour I'homme.

Plusieurs 6tudes ont 6galement r6vdl6 que l'endrine n'6tait pasg6notoxique.

Dans la plupart des 6tudes, I'endrine s'est r6v6l6e non t6ratogdne pourla souris, le rat ou le hamster, m€me i des doses toxiques pour la mdre oule fetus. La dose sans effet nocif observable a 6t6 fvalule iL 0,5 mglkg depoids corporel chez la souriset lerater e0,75 mgTkg de poids corporel chezleshamsters. L'endrinen'apas eu d'effets surla reproductiondes rats suivispendant trois gdn6rations qui enrecevaient dans letu nourriture i raison deZmg44g (soit environ 0,1 mgikg de poids corporel).

Un certain nombrre de mdtabolites de I'endrine sont plus ou moinstoxiques que le compos€ initial. Ainsi la delta-cdtoendrine est moinstoxique de l'endrine, en revanche la l2-c6toendrine est consid6r6e comme

230

EHC 130: Endrin

le m6tabolite le plus toxique de l'endrine pour les mammifbres, avec uneDLro par voie orale de 0,8-1,1 mg/kg de poids corporel chez le rat.

Effets sur I'homme

Plusieurs cas d'intoxication mortels ou non mortels consecutifs i unaccident ou ir une tentativede suicide ont6td observds. Les cas d'intoxicationaigud nonmortels resultant d'une surexposition accidentelle ont6t6 observ6schez les ouwiers d'wre usine de production d'endrine. On estime que parvoie orale, la dose mortelle est d'environ l0 mg/kg de poids corporel, unedose unique prise par voie orale de 0,25-1,0 mgtkg de poids corporel peutprovoquer des convulsions.

C'est au niveau du systBme nerveux central que l'endrine exerceprincipalement son action. Aprds exposition i dose toxique, des signesd'intoxication peuvent faire leur apparition et se manifestent sous la formed'un hyperexcitabilitd et de conwlsions, la mort pouvant survenir dans les2-12 heures suivant I'exposition si wr traitement appropri6 n'est pasinstitu6 immediatement. En revanche, aprds une intoxicationnon mortelle,la recupdration est rapide et compldte.

L'endrine ne s'accumule pas dans le corps humain de manidreimportante. Chez 232 travailleurs expos6s de par lewprofession, on n'a pasconstat6 d'effes inddsirables i long terme (duree d'exposition 4-27 ans)lors des examens m6dicaux pratiquds (durde de I'observation 2-29 ans).Leseul effet observ6, indirectement d'ailleurs, consistait en une stimulationrdversible des enzyrnes pharmacomdtabolisantes.

Des analyses ont 6t6 pratiqu6es dans de nombreux pays sur un grandnombre d'6chantillons de tissus adipeux, de sang et de lait matemel sansqu'il soit possible de mettre en 6vidence la prdsence d'endrine. Le Groupede travail attribue I'absence dendrine dans ces echantillons i la faibleexposition de la population g6ndral d ce pesticide et e sa mdtabolisationrapide.

En revanche la pr6sence d'endrine a 6tE &cel6e dans le sang (i desconcentrations atteignant 450 pg/litre) et dans les tissus adipeux (i la dosede 89,5 mg/kg) chez les personnes decddees d'une intoxication accidentelle.Dans les conditions normales, on n'a pas retrouv6 d'endrine chez lestravailleurs expos6s. Le seuil d'apparition des sympt6mes d'intoxication

231

2.

R6sum6

est estim6 i 50-1fi) pgllitre de sang. On perse que la demi-vie de I'endrinedans le sang est de l'ordre de 24 heures,

Conclusions

L'endrine est un irsecticide qui pr6sente une tGs forte toxicit6 aigu€.Il peut entrainer des intoxicatiorn graves en cas d'exposition excessive dued une manipulation n6gligente lors de sa production, de son utilisation oupar suite de Ia consommation daliments contaminds. L'exposition de lapopulation g6n6rale est principalement due i la pr6sence de r6sidus dansles denr6es alimentaires; toutefois on estime que la quantitd d'endrineing6r6e est en g6n6ral trds inf6rieure d la dose joumalidre admissible fix6epar le Comit6 FAO/OMS d'experts des r6sidus de pesticides. Il n'y a pas dedanger pour la population gdndrale qui rdsulterait d'une exposition de cegenre d I'endrine. Moyennant de bonnes m6thodes de travail et le respectdes mesure d'hygiEne et de s6curit6, l'endrine ne devrait pas constituer wrdanger pour les ouwiers expos6s.

Il est dvident que des rejets incontr6l6s d'endrine lors de la production,de la formulation et de l'utilisation de ce pesticide peuvent cr6er desprobldmes ecologiques dus i sa forte toxicit6. Il n'est pas possible d'6treaussi categoriqueencequi conceme leseffets quepeut avoirsonutilisationen agriculture sur la faune et la flore, encore que I'entrainement parruissellement du pesticide puisse constituer une menace pour les poissonset les oiseaux piscivores. Le d6clin des populations de certaines espbcesd'oiseaux a 6t6 attribu6 ilaprdsencederdsidus 6lev6sdedivers organochlor6sdans les tissus des adultes et dans les eufs. On a proc6d6 au dosage deI'endrine chez certaines de ces espdces; toutefois il est difficile de faire lapart des diff6rents organochlor6s qui sont en cause.

Recommandations

t . L'endrine ne doit €re utilisee qu'en cas de n6cessit6 et seulementlorsqu'il n'existe pas d'autre produit moins toxique.

Afin de pr6server la sant6 et le bien-€tre des travailleurs et de lapopulation g6n6rale, on ne doit confier la manipulation et l'6pandagequ'i des personnes bien encadr6es et bien formdes qui appligueront

232

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2.

3.

4.

EHC 13A: Endrin

des mesures de securitd convenables et dpandront le produitconform6ment aux rbgles de bonne pratique en la matidre.

Il convient de s'entourer de toute les pr6cautions n€cessaires lors de laproduction, de la formulation, de l'utilisation en agriculture et du rejetde I'endrine afin de contaminer le moins possible l'environnement eten particulier les eaux de surface.

Irs persorures qui sont habituellement exposdes i l'endrine doiventsubir des examens m6dicaux p6riodiques.

5. Il faut poursuiwe l'6tude 6piddmiologique des travailleurs expos6s'

Dans les pays oi I'on utilise encore de l'endrine, on devra contrdler lapr6sence de r6sidus dendrine dars les denr6es alimentaires.

Au cas oi l'on continuerait i utiliser de l'endrine, il faudrait obtenirdavantage de donndes sur la prdsence, la destin6e ultime et la toxicitede la l2-c6toendrine et de la delta-cdtoendrine.

233

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1 .

1 . 1

RESUMEN Y EVALUACION; CONCLUSIONES;RECOMENDACIONES

Resumen y evaluacl6n

Exposici6n

La endrina es un irsecticida organoclorado que se utiliza desde losaflos cincuenta para combatir muy divenas plagas agricolas, sob're todo enel algod6n armque nmbi6n en el uroz,la cafia de azricar, el maiz y otroscultivos. Se utiliza asimismo como rodenticida. Enel comercio se encuentraen forma de polvos, gntnulos, pastas y concentrado emulsionable.

La endrina se incorpora al aire principalmente por volatilizaci6n yanastre a6reo. En general, lavolatilizaci6n tiene lugardespu6s de aplicarlaa suelos y cultivos y depende de muchos factores, como el contenido demateria org6nica y agua del suelo, la humedad, el flujo de aire y lasuperficie cultivada.

La via m6s importante de contaminaci6n de las aguas de superficie esla escorrent(a desde el suelo. La contaminaci6nporprecipitaci6n en formade nieve o lluvia es insignificante. Puede producirse contaminaci6n localdel medio debida a efluentes industriales y pr6cticas de aplicaci6n pocometiculosas.

Laprincipal fuente de endrinaenel suelo es la aplicaci6ndirecta a 6stey a los cultivos. Puede quedar retenida, ser transportada o degradarse en elsuelo, atendiendo a diversos factores. La retenci6n m6s intensa se produceen suelos con contenido elevado de materia orgrinica. La persistencia de laendrina depende en gran medida de las condiciones locales; su semivida enel suelo puede llegar a los I 2 afios. La volatilizaci6n y la fotodescomposici6nson los principales factores de la desaparici6n de la endrina de lassuperficies del suelo. La luz del sol (luz ultravioleta) induce la formaci6ndel is6mero delta-cetoendrina. En verano, bajo insolaci6n intensa, seobserv6 que alrededor del 50Vo de la endrina se isomerizaba a estacetoendrina en wrplazo de siete dias. Se produce transformaci6n microbiana(en hongos y bacterias), especialmente en condiciones anaerobias,originr,{ndose la misma sustancia.

234

EHC 130: Endrln

Los invertebrados acudticos y los peces abaorbeq rdpidamente laendrina a partir del agua, si bien los peces expuestos transferidos a agua nocontaminada pierden el plaguicida rdpidamente. Se han registrado factoresde bioconcentraci6n de 14-18 000 tras una exposici6n continua. Losinvertebrados del suelo tambi6n absorben fdcilmente el compuesto.

La presencia ocasional de niveles reducidos de endrina en el aire y enlas aguas de superficie y de bebida en zonas agricolas reviste escasaimportancia desde el punto de vista de la saludptiblica. La fnica exposici6nque merece consideraci6n es la ingesta en la dieta. En general, no obstante,los niveles comunicados de ingesta se encuentran muy por debajo de laingesta diaria admisible de 0,0002 mg/kg de peso corporal, establecida en1970 (FAO/OMS, 1971).

Absorci6n, metabollsmo y sxcrecl6n

A diferencia de la dieldrina, su estereois6mero, la endrina se metabolizar6pidamente en los animales, y se acumula en muy pequefla cantidad en lasgrasas en comparaci6n con compuestos de estructura quimica andloga.

En la rata, tanto la absorci6n como Ia excreci6n tras la administraci6noral se producen rdpidamente; su semivida biol6gica es de l-6 dias, seginla dosis adminisrada. Al cabo de 6 dfas se alcanza un estado de equilibrioen el que la cantidad excretada es igual a la ingesta diaria. Se observandiferencias de un sexo a otro: los machos excretan endrina y metabolitoscon la bilis mucho m6s deprisa que las hembras, lo que produce unaacumulaci6nmenorenel tejido adiposode aqu6llos. Lasratasexcretanestecompuesto principalmente en las heces en forma de endrina,anti-12-hidroxiendrina, y un derivado hidroxilado durante las primeras horas (70-?57o); un tercer metabolito, la 12-cetoendrina, se acumula enlos tejidos. Elconejo excreta eI 50Vo de los metabolitos del compuesto enla orina,mientras que en la rata s6lo elZVo se excreta por esta via; en lasheces delconejo s6lo se detecta endrina sin alterar.

Las vacas a las que se administr6 endrina araz6n de 0,1 mg/kg de ladieta durante 2I dias excretaron hasta el65Vo en forma de metabolitos enlaorina,elZ0vo en las heces, parcialmente enforma de endrinano alterada,y el 34o en la leche, tambi6n principalmente en forma de endrina. Estasvacas presentaron niveles residuales de 0,003-0,006 mg/itro en la leche,0,001--0,002 mg/kg en la came, y 0,02-O,l mg/kg en la grasa.

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1.3

Resumen

En gallinas ponedoras a las que se administr6 endrina por via oralseobservaron niveles residuales (dependientes de la dosis administrada) dehasta 0,1 mg/kg en la carne, I mg/kg en la grasa, 0,24,3 mg/kg en loshuevos (yema), O,2mgkg en el rii6n y 0,5 mgftg en el higado. Salvo enel hfgado y el rif,6n, los residuos encontrados estaban formadosprincipalmente por endrina no alterada. Alrededor del50Vo de la endrinaadministrada se excret6 en las heces, principalmente en forma demetabolitos.

En el ser humano, la rata, el conejo, la vaca y la gallina, el principalmetabolito biotransformado de la endrina es la anti-12-hidroxiendrina,junto con su sulfato y su glucur nido conjugados. Se encontraron cuatrometabolitos m{s, si bien en cantidades muy reducidas. En los tejidoscorporales yen laleche se encuentra sobre todoendrina inalterada. Tras laaplicaci6n de este plaguicida a plantas, seidentificaron endrina inalteraday dos productos de transformaci6n hidr6filos.

Efectos en los organismos del medio ambiente

El efecto de la endrina en las bacterias y los hongos del suelo esm(nimo. Con dosisde 10-1Ofi)mg/kg desuelonose obsery6 efecto algunoenladescomposici6ndemateriaorgrinica,ladesnitrificaci6nni lageneraci6nde metano. La en&ina es sumamente t6xica para los peces, los invertebradosacu6ticos y el fitoplancr.on: los valores de la CLro a las 96 horas seencuentran en su mayor(apor debajo de 1,0 pg/litro. El nivel sin observaci6nde efectos mris bajo en un ensayo de ciclo biol6gico del crustdceoMysidopsis bahia se fij6 en 30 ng/iuo.

L,os ensayos comunicados sobre la toxicidad aguda de la endrina paralos organismos acudticos se llevaron a cabo en acuarios sin sedimentos;cabria esperar que la presencia de sedimentos atenuara el efecto de!insecticida. Los sedimentos muy contaminados ejercieron escaso efecto enlas especies de aguas libnes, lo que indica que la endrina ligada a lossedimentos tiene una biodisponibilidad reducida. Arin no se han llevadoa cabo ersayos en animales acudticos que viven en los sedimentos.

La DLro para mamiferos terrestres y aves oscila entre 1,0 yl0,0mg/kg depesocorporal. Lospatos silvestres alosqueseadministraron3,0 mg/kg de peso corporal durante 12 semanas no mostraron efectoalguno en la producci6n de huevos, la fertilidad o la eclosi6n.

236

EHC 130: Endrin

Ciertas especies de invertebrados acudticos, peces y mamiferos depequef,o tama o son resistentes a la toxicidad de la endrina; la expoSici6na diversos plaguicidas organoclorados llev6 a la selecci6n de estirpesresistentes a la endrina.

Se observaron muertes masivas de peces en zonas de escorrentfaagricola y descargas industriales; el declive de las poblaciones de pelicanospardos (en Luisiana, EE.UU.) y de golondrinas de mar (Thalasseus

sandvicensis) en los Pafses Bajos se ha atribuido a la exposici6n a la endrinaen combinaci6n con otras sustancias quimicas halogenadas.

Efectos en anlmales de experimentaci6n in vitro

La endrina es un plaguicida sumamente t6xico; los signos deintoxicaci6n son de car6cter neurot6xico. La DLro por via oral de la endrinade calidad t6cnica en animales de laboratorio oscila entre 3 y 43 mg/kgdepeso corporal; ta DLro por via cuti{nea en la rata es de 5-20 fnglkg pesocorporal. No se ha encontradoninguna diferencia en la toxicidad aguda porvia oral o cut6nea entre los productos de calidad t6cnica y los formulados(concentrado emulsionable y polvos humectables).

Se han llevado a cabo experimentos de breve duraci6n para estudiar latoxicidad por via oral en el rat6n, la rata, el conejo, el perro y animalesdom6sticos. En el rat6n y la rata, las dosis m6ximas toleradas durante6 semanas fueron 5 y 15 mg/kg de la dieta (equivalentes a 0,7 mg&g depesocorporal),respectivamente, Lasratas sobrevivierontrasunaexposici6na 1 mg/kg de la dieta (equivalente a 0,05 mglkg de peso corporal) durante16 semanas; los conejos murieron tras recibir dosis repetidas de I mgikgde peso corporal. En el perro, no se observ6 efecto alguno tras laadministraci6n de I mg/tg de la dieta (equivalente aproximadamente a0,025 mg/kg de peso corporal) durante m6s de 2 aflos.

La base neuro6gica de los signos de intoxicaci6n observados es lainhibici6n de la funci6n del 6cido gamma-aminobutirico (GABA) condosis reducidas. Al igual que otros insecticidas a base de hidrocarburosclorados, la endrina afecta tambi6n al higado, y se observa claramente Iaestimulaci6n de sistemas enzimdticos que participan en el metabolismo deotras sustancias quimicas, como lo demuestra, por ejemplo, la menorduraci6n del suerlo por hexobarbital en el rat6n.

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Besumen

Con dosis de 75-150 mglkg aplicadas por via curdnea en forma depolvo seco dtrante 2 horas al dfa se produjeron convulsiones y la muerteen el conejo pero sin iritaci6n cut6nea. Esta toxicidad sisr6mica sinirritaci6n en el lugar de contacto resulta muy notable.

Se han llevado a cabo en ratones y ratas estudios prolongados detoxicidad y carcinogenicidad. No se observ6 efecto carcinog6nico, peroestos estudios tenian ciertos defectos, entre ellos Ia reducida supervivenciade los animales. Elnivel sin observaci6n de efectos en cuanto a la toxicidaden un estudio de dos aflos de duraci6n en la rata fue de I mg/kg de la dieta(equivalente a unos 0,05 mg&g de peso corporal). No se demostr6 ningrinefecto de favorecimiento de tumores cuando se ensay6 la endrina encombinaci6n con cantidades subminimas de sustancias quimicas deconocido efecto carcinogdnico en los animales. El Grupo de Trabajoconcluy6 que los datos de que se dispone no bastan para indicar que laendrina supone un riesgo carcinogdnico para el ser humano.

En varios estudios se observ6 que la endrina no es genot6xica.

En la mayorfa de los estudios no result6 teratog6nica para el rat6n, larata o el h6mster, ni siquiera con dosis suficientes para provocar toxicidadmaterna o fetal. El nivel sin observaci6n de efectos adversos fue de0,5 mg/kg de peso corporal en rarones y ratas y de 0,75 mg/kg de pesocorporalenelhi{mster. I-aendrinanoindujoefectoalgwroen lareproducci6nderatas estudiadas durante tres generaciones cuando se administr6 a raz6nde2mgkg de la dieta (unos 0,1 mg&g de peso corporal).

Algunos metabolitos de la endrina tienen toxicidades agudas igualeso mds altas que el compuesto originario. El producto de transformaci6n, ladelta-cetoendrina, es menos t6xico que la endrina, pero la l2-cetoendrinase considera el metabolito miis t6xico en los mamiferos, con una DLro porvfa oral en la rata de 0,8-l,l mg/kg de peso corporal.

Efectos en el ser humano

Se hanproducido varios episodios de intoxicaci6n mortal y nomortal,tanto accidentales como suicidas. Los casos de intoxicaci6n aguda nomortal debida a exposici6n excesiva accidental se observaron en trabajadoresde una planta de fab'ricaci6n de endrina. Se ha calculado que la dosis quepor vfa oral provoca la muerte es de aproximadamente 10 mg/kg de peso

238

EHC 130: Endrln

corporal; la dosis rinica por vfa oral que provoca convulsiones se fij6 en0,25-1,0 mg/kg de peso corporal.

El lugar principal de acci6n de la endrina es el sistema nerviosocentral. La exposici6n del ser humano a una dosis t6xica puede producir alcabo de pocas horas signos y sintomas de intoxicaci6n tales comoexcitabilidad y convulsiones; la muertepuede producirse en las 2-12 horasque siguen a la exposici6n si no se administra inmediatamente el tratamientoapropiado. La recuperaci6n despu6s de una intoxicaci6n no mortal esrdpida y completa.

La endrina no se acumula en el cuerpo humano en grado significativo.No se comunicaron efectos adversos a largo plazo en 232 trabajadoresexpuestos (duraci6n de la exposici6n: 4-27 aflos) bajo supervisi6n m6dica(tiempo de observaci6n: 4-29 aios). El rinico efecto observado fueronpruebas indirectas de una estimulaci6n reversible de las enzimasmetabolizadoras de f6rmacos,

No se detect6 endrina en pr6cticamente ninguna muestra de tejidoadiposo, sangre y leche humana analizadas en numerosos pafses. El Grupode Trabajo atribuy6 la ausencia de endrina en las muestras humanas a labaja exposici6n de la poblaci6n general a este plaguicida y a su r6pidometabolismo.

La endrina se detect6 en la sangre (con concentraciones de hasta450 pgllitro) y en el tejido adiposo (en concentraciones de 89,5 mglkg) encasos de envenenamiento accidental mortal. No se encontr6 endrina en lostrabajadores en circtmstancias normales, El nivel umbral de endrina en lasangre por debajo del cual no se produce ningfn signo o sintoma deintoxicaci6n se ha fijado en 50-100 pgnitro. La semivida de la endrina enla sangre puede ser del orden de 24 horas.

Conclusiones

La endrina es un insecticida con elevada toxicidad aguda. Puedeprovocar envenenamiento grave encasos de exposici6n excesiva provocadapor lm manejo poco meticuloso durante su fabricaci6n y uso o por elconsumo de alimentos contaminados. El priblico estd expuesto a la endrinaprincipalmente por sus residuos en los alimentos; no obstante, los nivelesde ingesta de endrina que se han comunicado estdn por lo general muy por

239

3.

Resumen

debajo de la ingesta diaria admisible establecida por la FAO/OMS. Esasexposiciones en principio no constituyen un riesgo para la salud de lapoblaci6n general. Cuando se aplicanbuenas prdcticas de trabajo, medidashigi6nicas y precauciones de seguridad, es poco probable que la endrinasuponga un riesgo para los trabajadores expuestos.

Est6 claro que las descargas no controladas de endrina durante sumanufactura, formulaci6n y uso pueden originar graves problemasambientales asociados a su elevada toxicidad. Los efectos del uso agricoladel insecticida en la fauna y la flora estdn menos claros, si bien los pecesy las aves ictivoras est6n expuestos por la escorrentfa a partir de lassuperficies. El declive de las poblaciones de algunas especies de aves.sehaaribuido a la presencia de niveles elevados de residuos de diversoscompuestos organoclorados en los tejidos de adultos y en los huevos. Seha medido la endrina presente en algunas de estas especies, pero es muydificil separar los efectos de los distintos compuestos organocloradospresentes.

Recomendaclones

No debe utilizarse la endrina a menos que sea indispensable y s6locuando no se disponga de una altemativa menos t6xica.

Para la salud y el bienestar de los trabajadores y de la poblaci6ngeneral, el manejo y el uso de Ia endrina se confiariin s6lo a operariosbien supervisados y adiestados que apliquen las medidas de seguridadadecuadas y utilicen la endrina de acuerdo con las prdcticas agricolascolTectas.

La fabricaci6n, la formulaci6n, el uso agrfcola y la evacuaci6n deendrina se tratar6n cuidadosamente para reducir al minimo lacontaminaci6n del medio, en particular de las aguas de superficie.

Las personas expuestas regularmente a la endrina deben someterse arevisiones m6dicas peri6dicas.

Proseguir{n los estudios epidemiol6gicos sobre las poblaciones detrabaj adores expuestos.

L

2.

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4.

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7.

EHC 130: Endrin

En los pafses en los que arin se usa la endrina, deben vigilarse susresiduos en los alimentos,

Si sigue utilizr{ndose la endrina, debe obtenerse mds informaci6nsobre la presencia, el destino riltimo y la toxicidad de la I 2-cetoendrinay la delta-cetoendrina.

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