This report contains the collective views of an international group of
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    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

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

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

    World Health Orgnization
    Geneva, 1992

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    WHO Library Cataloguing in Publication Data


        (Environmental health criteria ; 129)

        1.Insecticides, Organochlorine - toxicity 2.Environmental exposure 

        ISBN 92 4 157129 2        (NLM Classification: WA 240)
        ISSN 0250-863X

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         1.1. Summary and evaluation
         1.2. Conclusions and recommendations


         2.1. Identity
         2.2. Physical and chemical properties
         2.3. Conversion factors
         2.4. Analytical methods



         4.1. Transport and distribution between media
         4.2. Biotransformation
              4.2.1. Soil
              4.2.2. Water


         5.1. Environmental levels
              5.1.1. Water
              5.1.2. Soil
              5.1.3. Food
            Plant products
            Products of domestic animals
            Market surveys
              5.1.4. Terrestrial and aquatic organisms
         5.2. General population exposure
         5.3. Occupational exposure


         6.1. Absorption
         6.2. Distribution
              6.2.1. Rat
              6.2.2. Dog
              6.2.3. Domestic fowl
              6.2.4. Cow
         6.3. Metabolic transformation
              6.3.1. Vertebrates
              6.3.2. Invertebrates
              6.3.3. Microorganisms
         6.4. Elimination and excretion in expired air,
              faeces, and urine
              6.4.1. Oral administration
              6.4.2. Parenteral administration
         6.5. Retention and turnover


         7.1. Single exposure
              7.1.1. Oral administration
              7.1.2. Dermal administration
              7.1.3. Parenteral administration
              7.1.4. Formulated material
              7.1.5. Metabolites
         7.2. Short-term exposure
              7.2.1. Oral administration
              7.2.2. Dermal administration
              7.2.3. Intraperitoneal administration
         7.3. Long-term exposure
              7.3.1. Rat
         7.4. Skin irritation
         7.5. Reproductive toxicity, embryotoxicity, and
              7.5.1. Mouse
              7.5.2. Rat
              7.5.3. Dog
         7.6. Mutagenicity and related end-points
         7.7. Carcinogenicity
              7.7.1. Mouse
              7.7.2. Rat
         7.8. Special studies
              7.8.1. Biochemical studies
              7.8.2. Neurotoxicity
              7.8.3. Pharmacological studies


         8.1. General population exposure
         8.2. Occupational exposure


         9.1. Microorganisms
         9.2. Aquatic organisms
         9.3. Terrestrial organisms
              9.3.1. Soil invertebrates
              9.3.2. Birds
            Acute toxicity
            Short-term toxicity
         9.4. Population and ecosystem effects
              9.4.1. Soil microorganisms
              9.4.2. Soil invertebrates






    Dr   L.A. Albert, Xalapa, Veracruz, Mexico

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

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

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

    Dr   Y.I. Kundiev, Research Institute of Labour Hygiene and
         Occupational Diseases, Kiev, USSR  (Vice-Chairman)

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

    Dr   H. Spencer, Office of Pesticides Programs, US Environmental
         Protection Agency, Washington, D.C., USA  (Chairman)

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

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

    Dr   C. Winder, National Institute of Occupational Health and
         Safety, Forest Lodge, New South Wales, Australia


    Dr   K.W. Jager, International Programme on Chemical Safety, World
         Health Organization, Geneva, Switzerland  (Secretary)

    Ms   B. Labarthe, International Register of Potentially Toxic
         Chemicals, United Nations Environment Programme, Geneva,

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


         Every effort has been made to present information in the 
    criteria documents as accurately as possible without unduly 
    delaying their publication. In the interest of all users of the 
    environmental health criteria documents, readers are kindly 
    requested to communicate any errors that may have occurred to the
    Manager of the International Programme on Chemical Safety, World
    Health Organization, Geneva, Switzerland, in order that they may be
    included in corrigenda.

                                *     *     *

         A detailed data profile and a legal file can be obtained from
    the International Register of Potentially Toxic Chemicals, Palais
    des Nations, 1211 Geneva 10, Switzerland (Telephone No. 7988400 or 


         A WHO Task Group on Environmental Health Criteria for 
    Isobenzan met at the World Health Organization, Geneva, from 23 to
    27 July 1990. Dr K.W. Jager welcomed the participants on behalf of
    Dr M. Mercier, Manager of the IPCS, and the three IPCS cooperating
    organizations (UNEP/ILO/WHO). The Task Group reviewed and revised
    the draft document and made an evaluation of the risks for human
    health and the environment from exposure to isobenzan.

         The first draft of this document was prepared in cooperation 
    between Dr E.A.H. van Heemstra-Lequin and Dr G.J. van Esch of the
    Netherlands. Dr van Esch prepared the second draft, incorporating
    the comments received following circulation of the first draft to
    the IPCS contact points for Environmental Health Criteria 
    documents. Dr K.W. Jager and Dr P.G. Jenkins, both members of the
    IPCS Central Unit, were responsible for the scientific content and
    technical editing, respectively.

         The assistance of Shell in making available to the IPCS and the
    Task Group its proprietary toxicological information on its products
    is gratefully acknowledge. This allowed the Task Group to make their
    evaluation on the basis of more complete data.

         The efforts of all who helped in the preparation and 
    finalization of the document are gratefully acknowledged.


    1.1  Summary and evaluation

         As far as is known, isobenzan, an organochlorine insecticide, 
    was only manufactured during the period 1958-1965. It was used from
    existing stocks for several years thereafter. At present, the only
    major sources of exposure are believed to be the original
    waste-disposal sites of industrial wastes or dredgings from 
    contaminated sediments.

         After isobenzan is applied to soil, a rapid initial loss
    occurs, after which the remaining compound decays at a much slower
    rate. It persists in soil from 2 to 7 years depending on the type of
    soil. Under laboratory conditions isobenzan decomposes in surface 
    water within a few weeks when exposed to natural or artificial 

         Soil, ground water, and surface water from polders built up 
    using sediment contaminated with organochlorines, including 
    chlorinated cyclodiene compounds, still contained minor residues of
    isobenzan some years later. In 1979-1980, no isobenzan was detected
    (detection limit: 0.01 mg/kg dry weight) in the sediment of rivers
    in the Netherlands. Following soil treatment, residues in crops are
    usually low (below 0.05 mg/kg crop), but higher levels may be found
    in some root crops (up to 0.2 mg/kg in carrots). In market surveys
    conducted during the time of the agricultural use of isobenzan, no
    residues were detected in the food items analysed (less than
    0.01 mg/kg).

         After cattle were allowed to graze pastures treated with 
    isobenzan, the resultant daily products contained residues of the 
    insecticide. Two samples of butter contained 0.07 and 0.15 mg 
    isobenzan/kg product, while the levels in whole milk were 0.005 to
    0.07 mg/kg. Dried milk, however, contained only 0.005 mg/kg. During
    the processing of dairy products, up to 50% of the residue was lost,
    depending on the type of treatment.

         No data are available on the levels of isobenzan in the blood 
    or adipose tissue of the general population. Operators exposed to 
    isobenzan in manufacturing and formulation plants had mean whole
    blood levels of up to 0.041 mg/litre. In whole blood  samples of
    people living in the neighbourhood of one plant, the  concentration
    of isobenzan was below the limit of detection (0.001 mg/litre).

         Isobenzan is readily absorbed through the gastrointestinal wall 
    and is transported in the blood as the unchanged compound.  
    Hydrophilic metabolites are formed, one of which has been identified
    as isobenzan lactone. Isobenzan accumulates in the tissues and
    organs of rats and dogs in the following order: fat > liver =
    muscle > brain > blood. The tissue concentrations of female rats

    are generally higher than those of males, especially in body fat.  
    The biological half-life in body fat was found to be 10.9 days in 
    male rats and 16.6 days in female rats. A female canine pup, whose
    blood contained 0.09 mg isobenzan/litre, showed convulsions 15 days
    after birth. The pup had only fed on the milk of its mother, a
    Beagle hound that had been dosed with isobenzan and whose milk
    contained 0.7 mg/litre. Similar effects on pups were seen in a rat
    reproduction study. Isobenzan is excreted via the milk of cows.

         Mosquito larvae and soil fungi metabolize isobenzan in the 
    same way as vertebrates, yielding isobenzan lactone as a 

         Isobenzan is very persistent in the environment and
    bioaccumulates. It is highly toxic to fish, shrimps, and birds. In
    the Netherlands, the country where isobenzan was manufactured,
    residues in the eggs of terns living along the Dutch coast ranged up
    to 0.45 mg/kg (mean, 0.09 mg/kg), while mean residues in mussels and
    fish were 0.05 mg/kg in 1965. Earthworm numbers were found to be
    reduced in field plots treated with isobenzan at 2 kg/ha.
    Nitrification was reduced, with a consequent increase in inorganic
    nitrogen, in soils treated with isobenzan in the field at 1 kg/ha,
    although laboratory studies showed no effect on nitrification at
    doses equivalent to 250 g/ha.

         The acute toxicity of isobenzan to mammals is high, both by the
    oral and percutaneous routes. The mode of action of its toxicity is
    an overstimulation of the central nervous system, resulting in
    convulsions. The acute toxicity of formulations of isobenzan 
    reflects the percentage of active ingredient present.

         Isobenzan is not a skin irritant, but some formulated products 
    may cause irritation.

         Limited short- and long-term oral studies in mice, rats, and
    dogs have shown that isobenzan may cause histological changes of the
    classical type of organochlorine intoxication in the liver. In a
    long-term rat study, a no-observed-effect level of 5 mg/kg diet
    (approximately 0.25 mg/kg body weight) was determined, and in a
    2-year dog study the no-observed-adverse-effect level (NOAEL) was
    0.025 mg/kg body weight.

         A one-generation reproduction study in rats indicated a NOAEL
    of 0.1 mg/kg diet (approximately 0.005 mg/kg body  weight). At a
    level of 1 mg/kg diet (approximately 0.05 mg/kg  body weight) the
    survival of pups decreased.

         No teratogenicity or mutagenicity studies have been reported.

         No carcinogenic potential was demonstrated in a 2-year oral 
    study on rats and in an oral study on mice, but these studies were 
    inadequate to evaluate carcinogenicity.

         The toxicological data base for isobenzan is incomplete. In
    general, the quality of the data is considered to be poor by today's
    standards and inadequate for an evaluation of the hazards to human
    health or the environment.

         Data on exposed humans are limited to studies on workers in a
    factory in the Netherlands during the manufacture and formulation of
    isobenzan and related "chlorinated cyclodiene insecticides". No
    cases of skin irritation were reported. In several cases of
    intoxication, convulsions occurred but the changes in the EEG
    pattern were reversible. The intoxication threshold level (for 
    convulsions) was estimated to be 0.015 mg isobenzan/litre blood, and
    the biological half-life of isobenzan in human blood was estimated
    to be of the order of 2.8 years.

    1.2  Conclusions and recommendations

         Isobenzan is highly toxic and very persistent. The available
    information on the hazards of isobenzan is incomplete, but is,
    nevertheless, sufficient to indicate that the hazard it poses to
    those who handling it and to the environment is such that no human
    or environmental exposure to this substance, used either as an
    insecticide or for any other purpose, should be allowed.


    2.1  Identity

    Chemical formula         C9H4OCl8

    Chemical structure
         and spatial


    Chemical names           1,3,4,5,6,7,8,8-octachloro-4,7-methylene-

    Common synonyms          BAS-4402; CP 14957; ENT-25 545; OMS-206;
                             OMS-618; SD-4402; WL 1650; preparation 948

    Common trade name        Telodrin (technical product), Omtan

    Purity (technical)       not less than 95% (w/w)

    RTECS registry
    number                   PC1225000

    CAS registry number      297-78-9

    2.2  Physical and chemical properties

         Some physical and chemical properties of isobenzan are given in
    Table 1.

    Table 1. Some physical and chemical properties of isobenzan

    Physical state                     crystalline powder

    Colour                             whitish to light brown

    Odour                              mild "chemical" odour

    Relative molecular mass            411.73

    Melting point (°C)                 120-122

    Flash point                        non-flammable

    Explosion limits                   non-explosive

    Relative density                   1.87

    Vapour pressure (20 °C)            6.7 x 10-4 Pa (5 x 10-6 mmHg)

    Solubility in water                practically insoluble

    Solubility in organic              slightly soluble in kerosene and ethanol; soluble
    solvents                           in acetone, benzene, toluene, xylene, heavy aromatic
                                       naphtha, and ethyl ether

    Stability                          relatively stable to acids; dehydrochlorination may
                                       occur under strong alkaline conditions
    2.3  Conversion factors

         1 ppm  = 17 mg/m3 at 20 °C
         1 mg/m3 = 0.06 ppm at 20 °C

    2.4  Analytical methods

         Analytical methods for the extraction, preparation, and
    determination of residues of isobenzan in crops, animal products,
    and soil using gas-liquid chromatography with electron-capture
    detection have been described in detail by Elgar (1966) and Anon
    (1974). The limit of determination is 0.01 mg/kg.

         Kadoum (1968) described a rapid micromethod of sample clean-up
    for gas-chromatographic analysis of isobenzan in ground water, soil,
    and plant and animal extracts, using activated silica gel of high

    purity. The percentage recovery was from 90% to 99% depending on the
    quantity of eluate (305 v/v benzene in hexane) used. The limit of
    determination in soil and plant or animal tissue was 0.01 mg/kg and
    in water was 0.01 µg/litre.

         Suzuki  et al. (1974) analysed different types of pesticides
    in extracts from crops or soil and separated them into a number of
    groups by column chromatography (prior to thin-layer chromatography)
    to obtain a systematic identification and determination of these
    compounds. Silica gel was used for column chromatography and
    thin-layer plates. For gas chromatographic separation, glass columns
    packed with different absorbents were used. Electron capture
    detection and a 63Ni source were used for the determination.

         An advanced residue method, i.e. automated glass capillary gas
    chromatography with electron-capture detection, was described by
    Tuinstra & Traag (1979) for use with soil, vegetable material, milk
    fat, and feed stuffs.

         Wegman & Hofstee (1982) used capillary gas chromatography with
    electron-capture determination for soil and river sediment samples.

         The analysis of isobenzan in blood can be carried out according
    to the method of Richardson  et al. (1967) using gas-liquid
    chromatography with electron-capture determination. The method is
    sufficiently sensitive to detect isobenzan levels of less than
    1 µg/litre blood.

         Confirmation tests should be carried out using an appropriate
    method (Anon, 1974).


         Telodrin was the registered trademark for the chlorinated
    cyclodiene insecticide isobenzan. Isobenzan was only manufactured by
    Shell during the period 1958-1965, but it was used for several years
    thereafter from existing stocks. The major sources of exposure at
    present appear to be the original waste disposal sites of industrial
    wastes or dredged muds from contaminated areas.


    4.1  Transport and distribution between media

         The environmental transport of isobenzan was investigated in a
    slow sand filtration system used for the purification of ground
    water. The first filter consisted of gravel and the second of sand.
    Isobenzan was applied to the inlet water at a concentration of
    1-10 µg/litre for 2 consecutive weeks. Fifty days elapsed after the
    isobenzan treatment before it was no longer detectable in the
    out-stream (Bauer, 1972).

    4.2  Biotransformation

    4.2.1  Soil

         In a study by Bowman  et al. (1965), the behaviour of
    isobenzan in soil was investigated in laboratory tests. Eight types
    of soil were used ranging from sand to sandy clay, the percentage of
    sand varying from 93 to 56% and the percentage of clay from 4 to
    35%. Following percolation with hexane, the percentage of isobenzan
    in the eluate fraction was shown to decrease with increasing content
    of clay in the soil (starting at about 30% clay). Except in the case
    of sand with a high organic matter content (6-19%), no isobenzan was
    recovered from the dry soils after 4-8 days of exposure at 45 °C.
    When the soils were moistened with water and exposed at 45 °C for 4
    days, degradation was markedly diminished, with the exception of the
    sand with high organic matter.

         After isobenzan is applied to soil (chalky loam, sandy loam,
    and peat), a rapid initial loss occurs, probably due to sublimation.
    The remaining compound then decays at a much lower rate, probably
    having been adsorbed onto soil particles (Elgar, 1966).

         The persistence of isobenzan in soil (95% disappearance) is 2-7
    years (average 4 years) following an average dosage of 0.25-1 kg
    isobenzan/ha (Edwards, 1965).

    4.2.2  Water

         When river water (pH 7.3) treated with 10 µg isobenzan/litre
    was kept at room temperature in closed glass containers and exposed
    to natural and artificial light, 25% of the isobenzan remained after
    one week and 10% after 2 weeks. After the fourth week, no isobenzan
    was detectable (detection limit: 50 ng/litre) (Eichelberger &
    Lichtenberg, 1971).


    5.1  Environmental levels

    5.1.1  Water

         During the period 1969-1977, 1826 samples of surface water,
    ground water, and rain water were taken at 99 sampling sites all
    over the Netherlands, with special emphasis on the Rivers Rhine and
    Meuse. Isobenzan was not present at measurable concentrations in any
    of the samples (Wegman & Greve, 1980).

         Soil samples were taken in 1977 to depths of 1-7 m from a
    polder near Rotterdam that had been filled with material dredged
    from the Rotterdam harbours between 1959 and 1976. In the ground
    water, released from the samples by pressure, the concentration of
    isobenzan in samples obtained from depths of 1, 3, and 5 m was less
    than 0.05 µg/litre. The concentrations in those from depths of 2 and
    7 m were 0.21 and 0.07 µg/litre, respectively. The surface water
    taken from the drainage system of the polder contained
    0.03 µg/litre. Most of the isobenzan in the polder was bound to
    solids, the ratio of bound to dissolved isobenzan being over 11 000
    to 1 (Kerdijk, 1981).

         When 60 samples of water from 19 rivers and their estuaries
    collected in Japan in 1974 were analysed for isobenzan, none was
    detected (detection limit: < 0.1 µg/litre) (Japanese Environmental
    Agency, 1975).

    5.1.2  Soil

         In a study by Elgar (1966), chalky loam, sandy loam, and peat
    were treated with 0.5 kg isobenzan/ha (as emulsifiable concentrate)
    once in 1961 or by three annual applications in 1961-1963. About 15%
    of the initial residue remained after one year. More than half this
    amount was still present 2 years later (Table 2).

         In a Dutch monitoring programme, 145 sediment samples were
    taken by dredge at 36 sampling sites in tributaries of the Rhine
    River, Western Scheldt, and in some harbour basins of Rotterdam
    during 1979-1980. None of the samples contained isobenzan (the
    detection limit was 0.01 mg/kg soil on a dry weight basis) (Wegman &
    Hofstee, 1982).

         Sixty samples of bottom deposit from 19 rivers and their
    estuaries in Japan collected in 1974 did not contain any isobenzan
    (detection limit: 0.01 mg/kg) (Japanese Environmental Agency, 1975).

    Table 2. Residues of isobenzan in 3 soil types after treatment with 0.5 kg isobenzan/ha

                                                              Time of sampling

    Soil        Years of               Spring    Autumn    Spring    Autumn    Springa   Autumn    Spring
    type        treatment              1961      1961      1962      1962      1963      1963      1964

    Chalky      1961                   1.1       0.6       0.6       0.3        0.2      0.2       0.2
    loam        1961, 1962, 1963                           1.4       0.7      0.3/0.9    0.5       0.3

    Sandy       1961                   0.6       0.2       0.1       0.1        0.1      0.1       0.2
    loam        1961, 1962, 1963                           0.5       0.3      0.2/0.9    0.4       0.3

    Peat        1961                   4.2       0.3       0.2       0.2        0.3      0.3       0.3
    soil        1961, 1962, 1963                           1.2       0.7      0.2/1.6    1.1       0.5

    a The two values represent residues before and after re-spraying.

    5.1.3  Food  Plant products

         Residue data, resulting from both foliar and soil treatment,
    for a variety of crops have been reported (Shell, 1964).

    a) Residues in crops: Foliar treatment

         The magnitude of residues found on foliage or fruit is affected
    by a number of factors. Crops having a large volume but a small
    surface area tend to start off with a low concentration of
    isobenzan. When crops have a rough (peach) or waxy (blackcurrant,
    cabbage) surface, isobenzan appears to be less readily removed by
    weathering than it is from smooth-skinned crops like tomatoes.

         The rate of growth of the edible part of the crop is a
    consistently significant factor, as is the application rate and
    concentration. There is no evidence that isobenzan is translocated
    or absorbed by plants and the rates of dissipation can be explained
    by weathering of surface deposits, with some adsorption by cuticular
    fats retarding this process. The period after the last application
    required for the residue level to fall to below 0.05 mg/kg product
    varies from 14 to 65 days, depending on the factors mentioned above.

         Once a crop has been harvested, the residues present may be
    further reduced or eliminated before consumption by various
    subsequent processes. Washing can remove 60% of isobenzan residues
    on broccoli. Isobenzan is removed when fruit and vegetables (such as
    tomatoes) are processed to produce juice. Canning and freezing
    processes (involving washing or blanching) also reduce residue
    levels. Peeling of fruits (such as peaches) and discarding outer
    leaves of vegetables (cabbage and lettuce) reduce the residue levels
    significantly. In the case of tobacco, substantial quantities of
    isobenzan are lost during both the curing and smoking. Cotton-seed
    has very low levels of residues (of the order of 0.01 mg/kg product)
    and the major part is found in the crude oil after processing
    (Shell, 1964).

         In 1964, cotton was treated up to 12 times with Telodrin dust
    or emulsifiable concentrate at a dose of up to 350 g isobenzan/ha in
    Guatemala, Mexico, and Nicaragua, and the seeds were harvested 17
    days after the last treatment. The cotton seed oil contained
    isobenzan residues of < 0.05 mg/kg (Elgar, 1965; Hughes, 1965).

         Isobenzan residues of less than 0.05-1.5 mg/kg were found in
    tobacco leaves grown in Australia during the period 1961-1964. 
    Cigarettes contained 0.2-0.3 mg/kg and pipe tobacco 0.06 mg/kg
    (Buick, 1964).

    b) Residues in crops resulting from soil treatment

         When potatoes (in India and the United Kingdom) and sweet
    potatoes (in South Africa) were grown in soil treated before
    planting in 1964 with Telodrin dust or emulsifiable concentrate at
    up to 3 kg isobenzan/ha or treated three times with Telodrin
    emulsifiable concentrate at 200 g isobenzan/ha, the residues were
    near the limit of detection (0.05 mg/kg crop) (Murphy & Standen,
    1964; Buick, 1965; Buick & Cole, 1965).

         In the United Kingdom, chalky loam, sandy loam, and peat were
    treated with diluted 15% Telodrin emulsifiable concentrate at a
    level of 0.5 kg isobenzan/ha. This was immediately incorporated by
    harrow and, directly after, the plots were sown with cabbage,
    carrot, onion, and sugar beet seed. Potatoes and celery were planted
    at a later date. The plots were treated either in 1961 only or in
    1961, 1962, and 1963. Residues were found in crops grown in both
    loam soils, but not in those grown in peat, and only in root crops
    (at a maximum of 0.05 mg/kg crop) after treatment in 1961. The
    residues did not increase markedly with annual retreatment, the
    maximum concentration found being 0.08 mg/kg in carrots (Elgar,

    c) Residues in crops resulting from contaminated soils

         Crops and the soil in which they had been grown were sampled at
    harvest in 1976 from Dutch polders that had been built up during
    1967-1969 with sediments dredged from the River Rhine and from a
    harbour basin near a pesticide manufacturing plant. No residues of
    isobenzan were detected in onions, brussel sprouts, or potatoes
    (detection limit: 0.01 mg/kg), whereas carrots contained residues of
    up to 0.09 mg/kg. The corresponding soil samples contained isobenzan
    residues of between 0.01 and 3.5 mg/kg (dry weight basis). The ratio
    of the concentration in carrots to that in soil, both calculated on
    a dry weight basis, was 0.26 (Wegman  et al., 1981).  Products of domestic animals

         Pasture in Venezuela was treated with isobenzan at an average
    dosage rate of 300 g/ha, and cattle were reintroduced 3-6 months
    later. Analysis of the dairy products showed two samples of butter
    containing residues of 0.07 and 0.15 mg/kg, respectively. In milk,
    the residues ranged from 0.005 to 0.07 mg/kg, while dried milk
    contained negligible residues (0.005 mg/kg) (Standen & Elgar, 1965).

         Heat treatment of various dairy products manufactured from milk
    containing 0.8 mg isobenzan/kg (18 mg/kg on fat basis) was found to
    cause residue losses. Between 40% and 50% of the residues were
    destroyed in evaporated milk and 10-20% of the residues during
    processing of the milk for dry whole milk (Stemp & Liska, 1966).

         No residues of isobenzan could be detected in chicken meat 
    after white meat containing 0.2 mg/kg or dark meat containing
    0.5 mg/kg had been cooked (McCaskey  et al., 1968).

         In Victoria, Australia, in 1963, dairy pasture was sprayed with
    140 g isobenzan/ha and left for 3 weeks before dairy cattle were
    reintroduced. Within 2 days, toxic symptoms (circling, rolling of
    eyes, salivation, convulsions) were observed in dairy cattle that
    had consumed treated grass. Deaths occurred in cattle and calves and
    in cats, rabbits, poultry, and dogs. A 10-month old baby, fed on
    milk from the cows, developed an illness characterized by
    irritability and persistent crying. Milk from one cow with signs of
    intoxication had an isobenzan level of 1 mg/litre. Analysis of
    isobenzan residues in farm milk (representing milk from many cows)
    ranged up to 5 mg/litre, although most values were in the range of
    0.05 to 0.2 mg/litre. Residues of isobenzan were still present in
    some milk samples 14 months later. Isobenzan was also detected in
    cow adipose tissue (10 mg/kg), cat liver (4.5 mg/kg), and calf liver
    (7.5 mg/kg). Isobenzan levels in surface water used by the cattle
    were very low (0.0002 mg/litre) (Shell, 1963).  Market surveys

         Food items covering the important constituents of the local
    diet (e.g., potatoes, rice, wheat, onions, different types of beans,
    fruit, beef, lamb, milk, cheese, ground-nut products, maize, and
    sugar cane) were collected in Venezuela (1966), Mexico (1967),
    Nicaragua (1967), Spain (1967), and India (1968). Residues of
    isobenzan in these products were below the limit of detection
    (0.01 mg/kg) (Bull & Marlow, 1967; Bull & Ramsden, 1967; Elgar &
    Holland, 1967; Marlow  et al., 1968; Mathews, 1969).

         Isobenzan was not detected in market-basket surveys conducted
    by the Food and Drug Administration in the USA during the period
    1980-1990 (Burse, 1990, personal communication to the IPCS).

         Cured tobacco from Costa Rica contained 1.3 mg isobenzan/kg
    (Mathews & Cole, 1966).

    5.1.4  Terrestrial and aquatic organisms

         Fish, mussels, and the eggs of various species of tern were
    collected along the north coast of the Netherlands and analysed for
    residues of chlorinated hydrocarbon insecticides. The mean isobenzan
    residues in eggs were 0.09 mg/kg (range, 0.02-0.45 mg/kg) in 1965
    and 0.06 mg/kg (range, 0.02-0.12 mg/kg) in 1966. The mean residues
    in composite samples of fish (sprat, juvenile herring, and sand eel)
    were 0.05 mg/kg (range, 0.04-0.07 mg/kg) in 1965 and 0.02 mg/kg

    (range, 0.01-0.05 mg/kg) in 1966.  Mussels (Mytilus edulis) sampled
    in 1966 did not contain any residues of isobenzan (detection level:
    0.003 mg/kg), but mussels sampled at one particular place in 1965
    contained 0.11 mg/kg (Koeman  et al., 1967, 1968).

         Residues in the livers of sandwich terns found dead in the
    Dutch Wadden Sea during the summers of 1965 and 1966 amounted to as
    much as 3.8 mg/kg isobenzan (average, approximately 0.75 mg/kg)
    (Koeman  et al., 1967).

         Sixty samples of fish and shellfish collected in 19 rivers and
    their sea estuaries in Japan in 1974 contained no isobenzan
    (detection limit: 0.005 mg/kg) (Japanese Environmental Agency,

    5.2  General population exposure

         A housing estate of about 800 houses and public buildings was
    built directly on a 4-m thick layer of harbour sludge in the
    Netherlands in 1983. The area was raised during the period 1962-1964
    by sludge originating from about 20 harbour basins in Rotterdam and
    the industrial area around the Nieuwe Waterweg. In the sludge,
    organic solvents, polyaromatic hydrocarbons, heavy metals, and
    chlorinated cyclodiene insecticides including isobenzan were
    detected. One-third of the soil samples collected in the gardens
    (71 locations), 0-40 cm below the surface, contained chlorinated
    cyclodiene insecticides with a mean concentration of 1.2 mg/kg and a
    maximum concentration of 19.5 mg/kg dry weight (Van Wijnen &
    Stijkel, 1988).

         From the residue data presented in section 5.1.3, it appears
    that exposure of the general population via food was very low at the
    time when isobenzan was used agriculturally. Exposure from
    environmental sources must also have been minor. For example, the
    concentration of isobenzan in the blood of 10 people living in the
    vicinity of an isobenzan formulation plant in Venezuela was below
    the limit of determination (0.001 mg/litre) (Davies, 1966a,b).

    5.3  Occupational exposure

         In a study carried out in 1965-1968 at a formulation plant in
    Venezuela, 229 blood samples were taken from operators formulating
    isobenzan and related chlorinated hydrocarbon insecticides. The
    concentrations of isobenzan in blood fluctuated during this period
    due to variations in the formulations being prepared at the plant.
    The mean concentrations in whole blood ranged from 0.004 to
    0.033 mg/litre, the maximum concentration being 0.045 mg/litre
    (Davies, 1966a,b; Crabtree, 1968).

         Isobenzan levels in the range of < 0.002 to 0.041 mg/litre
    were found in the blood of operators at a manufacturing and
    formulation plant in the Netherlands (Jager, 1970).


    6.1  Absorption

         In studies using everted sacs of rat ileum, colloidal solutions
    and dispersions of isobenzan labelled with 14C were absorbed
    through the intestinal wall. The maximum uptake occurred in the
    middle segment of the ileum (Hathway, 1965).

         Following an oral dose of 14C-isobenzan, only a small
    proportion (< 10%) of the label was found in the thoracic lymph
    duct, the remainder being in the hepatic portal blood (Hathway,

    6.2  Distribution

         Isobenzan is approximately 4000 times more soluble in rabbit
    serum than in water, and it has been shown that, during transport in
    the blood of rats and rabbits, isobenzan is associated with some
    serum proteins (albumin and alpha-globulin in the rabbit and
    albumins in the rat) and with constituents of the red blood cell,
    mainly haemoglobin. The ratio of the distribution of the insecticide
    between plasma and cells was shown to be approximately 2:1, this
    ratio remaining constant at different intervals after administration
    and at different concentrations. Gas chromatography showed that
    unchanged isobenzan was transported in the blood (Moss & Hathway,
    1964; Hathway, 1965).

    6.2.1  Rat

         In an extensive study, Carworth Farm rats were fed diets
    containing isobenzan (96%) (5, 15.9, or 25 mg/kg) for periods of 44
    to 224 days followed by a control diet for periods of up to 64 days.
    Analyses of tissues at several intervals during feeding showed the
    concentrations of isobenzan to be in the following order: fat >
    liver = muscle > brain > blood. Concentrations in females were
    higher than those in the males, especially in the fat. There was a
    significant correlation between the concentration of isobenzan in
    blood and in other organs, plausibly attributed to a dynamic
    equilibrium. The biological half-life in body fat was 10.9 days in
    male rats and 16.6 days in female rats (Robinson & Richardson,

         When male and female rats were given a single intravenous
    injection of 14C-isobenzan (15 µg/kg body weight), the
    radio-activity in the blood of males 48 h later was 0.04% of the
    applied dose and in females was 0.37%. The radioactivity in the
    organs and tissues ranged between 0.01 and approximately 1.5% of the
    applied dose, concentrations being lower in females than in males.

    In abdominal fat, the concentrations were 19.2% in males and 26.6%
    in females and, in muscle, 12.3% and 9.3%, respectively. The
    concentration in subcutaneous fat was about half of that in
    abdominal fat (Kaul  et al., 1970).

         Isobenzan rapidly crosses the placental barrier in pregnant
    rats. Labelled isobenzan was found in fetal blood within 5 min of an
    intravenous administration into the ear vein of the mother (Hathway,

         Fetuses removed by caesarean section from Carworth Farm rats
    fed a dietary isobenzan concentration of 5 mg/kg in a reproduction
    study carried out by Chambers (1962a,b) (section 7.5.2) contained
    0.1-0.13 mg isobenzan/kg tissue (Stevenson, 1964).

    6.2.2  Dog

         In a study by (Worden, 1969), groups of six Scottish terriers
    (males and females) were given daily isobenzan doses of 0.025 or
    0.1 mg/kg body weight by gavage for 2 years (section At
    the end of the study the distribution of isobenzan in the tissues
    was examined, and the concentration was highest in body fat and
    least in blood (Table 3). There was a significant correlation
    between the concentrations in blood and those in other tissues. The
    storage ratio (concentration in body fat/concentration in diet) did
    not show any significant differences between the sexes or between
    the two dose levels.

    Table 3.  Mean concentrations (mg/kg) of isobenzan in tissues of dogs
              dosed orally with isobenzan for 2 years

    Dose                Fat       Muscle    Liver     Brain     Blood

    0.025 mg/kg body    2.9       0.25      1.2       0.2       0.02

    0.1 mg/kg body      9.5       0.8       4.2       0.4       0.04
         The first litter from a female Beagle hound dosed with 0.08 mg
    isobenzan/kg body weight per day (section 7.5.3) consisted of one
    male, one female, and one still-born male. The concentrations of
    isobenzan in the brain, liver, muscle, heart, and kidneys of the
    still-born pup were below 0.2 mg/kg, with the liver containing the

    highest level of 0.16 mg/kg. The female pup, which only fed on the
    mother's milk, showed convulsions 15 days after birth and was killed
    at 17 days of age. The blood contained 0.09 mg isobenzan per kg and
    the urine 0.02 mg/kg. The concentrations in organs and tissues were
    less than 1 mg/kg, the highest levels being in muscle (0.94 mg/kg),
    liver (0.65 mg/kg), and fat (0.48 mg/kg). The milk from the mother
    contained 0.7 mg/litre as whole milk and 3.4 mg/kg on a fat basis.
    The remaining pup showed no ill effects. Four males and two females
    in further litters also showed no ill effects (Brown & Richardson,

    6.2.3  Domestic fowl

         In a study by McCaskey  et al. (1968), six Leghorn hens
    received, in a gelatin capsule on each of 5 days, an amount of
    isobenzan (94% purity) equivalent to 10-15 mg/kg of the average
    weight of daily feed consumed. Eggs were collected on days 2-8, and
    the hens were killed 3 days after the last dose. Residues in tissues
    and eggs are given in Table 4.

    Table 4.  Concentrations of residues (mg/kg products) in tissues
              and eggs of hens dosed orally with isobenzan 

    Tissue              Residue concentration (mg/kg)

    Abdominal fat       10.6

    White meat          0.2 (on fat basis: 3.4)

    Dark meat           0.5 (on fat basis: 4.3)

    Egg yolk            0.1 on day 4; 0.4 on day 5; 0.5 on day 7
                        0.7 on day 8
    6.2.4  Cow

         Three Jersey cows were fed for 28 days at concentrations of
    technical isobenzan of 0, 0.005, or 0.02 mg/kg in their daily ration
    (average ration, 20 kg per cow). Residues found in the milk of the
    cow fed 0.005 mg/kg increased from 0.4 µg/litre to 2 µg/litre at the
    end of the feeding period and decreased rapidly thereafter. Higher
    residues of up to 7.7 µg/litre were present in the milk from the cow
    fed 0.02 mg/kg, which decreased to 1.5 µg/litre whole milk 10 weeks
    after the last day of dosing (Hardee  et al., 1964).

         Following the consumption of feed contaminated with relatively
    low concentrations of isobenzan, the concentration in milk rose
    rapidly within a few hours to days, levelling off at a plateau
    characteristic for each concentration in the diet. The average
    milk/diet ratio for isobenzan was 0.4 to 0.5 for feeding levels of
    0.005 to 0.02 mg/kg diet (Biehl & Buck, 1987).

         In a study by Bishop & Huber (1964), four groups of three
    lactating Holstein cows were fed 0, 0.02, 0.06, or 0.15 mg
    isobenzan/kg (corresponding to 0.47, 1.38, or 3.38 mg/cow per day)
    in their daily ration for 90 days. The concentrations in the milk
    were directly proportional to the dietary level. Increases in
    concentration were noted during the entire treatment period for the
    0.06- and 0.15-mg/kg feeding levels, reaching 0.033 and
    0.071 mg/litre of milk. Trace amounts (up to 0.008 mg/litre) were
    found in the milk from cows fed 0.02 mg/kg. At the highest dose,
    residues of 0.016 mg/litre were still present in the milk 60 days
    after treatment, while in the groups fed 0.06 and 0.02 mg/kg, the
    residues were then negligible. Residues in fat from biopsies taken
    88 days after the treatment finished reflected the exposure levels,
    being 0.11, 0.26, and 0.53 mg/kg tissue for the three levels.

    6.3  Metabolic transformation

    6.3.1  Vertebrates

         The radioactive residue present in the urine and faeces of rats
    treated with a single intravenous injection of 14C-isobenzan
    consisted of a hydrophilic metabolite that, after hydrolysis, gave
    isobenzan lactone (Kaul  et al., 1970).

         It is probable that both chlorine atoms on the tetrahydrofuran
    ring are first replaced by hydroxyl groups. The resulting "acetale",
    an unstable intermediate, is converted to the gamma-lactone (Korte,
    1967) (Fig. 1).

    6.3.2  Invertebrates

         Mosquito larvae  (Aedes aegypti) metabolize isobenzan,
    labelled with 14C in the hexachloropentane ring or at the 1,3
    position, to a metabolite more hydrophilic than that produced by
    microorganisms. This metabolite consists of at least three
    components. The hydrolytic product of one of these components was
    identified as isobenzan lactone (Korte, 1963, 1967; Korte & Stiasni,

    FIGURE 1

    6.3.3   Microorganisms

         Isobenzan labelled with 14C in the hexachloropentane ring or
    at the 1,3 position is metabolized by the fungi Aspergillus niger,
     Aspergillus flavus, Penicillium chrysogenum, and Penicillium
     notatum to isobenzan lactone, the same metabolite as found in
    animal metabolism studies (Korte, 1963; Korte & Stiasni, 1964).

    6.4  Elimination and excretion in expired air, faeces, and urine

    6.4.1  Oral administration

         In a study by Korte (1963), ten rabbits received in their diet
    2 mg 14C-isobenzan, diluted with non-radioactive isobenzan, every
    2 days to a total amount of 25-30 mg per rabbit. After 3 months,
    about 50% of the total radioactivity administered had been excreted,
    mainly in the urine. On the other hand, rats excreted most of the
    radioactivity via bile into the gastrointestinal tract and excreted
    these products with the faeces. No unchanged isobenzan was excreted,
    only hydrophilic metabolites.

    6.4.2  Parenteral administration

         When Carworth Farm rats received daily intraperitoneal
    injections of isobenzan (98% purity) of 0.25, 1, or 2 mg/kg body
    weight 5 days per week for 2 weeks (section 7.2.3), they excreted
    less than 1% of the daily dose as unchanged isobenzan in the faeces
    (Brown  et al., 1962).

         In a study by Kaul  et al. (1970), male and female rats
    received a single intravenous injection of 15 µg 14C-isobenzan/kg
    body weight. The male rats excreted 1% of the applied radioactivity
    in the urine and 12% in the faeces within 48 h, while the females
    excreted 5% and 11%, respectively.

         After having been administered intravenously to rats with
    cannulated bile ducts, 14C-isobenzan was excreted as hydrophilic
    metabolites in the bile (Korte, 1963, 1967).

         Male rabbits given an intravenous injection of 14C-isobenzan
    (241 µg/kg body weight) excreted 12% in the urine and 1% in the
    faeces within 96 h (Kaul  et al., 1970).

    6.5  Retention and turnover

         The absorption of isobenzan into the body is determined by
    measuring the insecticide in the blood. No human studies exist
    relating the concentration of isobenzan in the blood at the state of
    equilibrium to the total daily intake or relating the concentration
    of isobenzan in the blood to that in the tissues. However, in
    experimental animals, such relationships have been determined. Thus,
    in human beings, measurement of the blood concentration of the
    insecticide at the state of equilibrium is assumed to reflect total
    absorption by all routes (skin, pulmonary, and oral exposure) as
    well as the storage level in adipose tissue, thereby providing a
    measure of the total body burden of isobenzan.

         From human data, it is estimated that the biological half-life
    of isobenzan in blood is of the order of 2.8 years (Jager, 1970)
    (section 8.2).


    7.1  Single exposure

    7.1.1  Oral administration

         In rats, the first signs of toxicity were evident approximately
    1 h after the administration of a lethal dose and consisted of
    lethargy followed by muscular twitching, laboured breathing, and,
    finally, general convulsions. The majority of deaths occurred within
    the first 20 h after administration. No specific changes were
    observed in the organs of fatally intoxicated animals. Signs of
    intoxication were similar in mice, rats, guinea-pigs, cats, dogs,
    and chickens. Surviving animals recovered completely (Brown et al.,
    1962; Worden, 1969).

         Oral LD50 values for the various animal species range from
    1.6 to 10 mg/kg and are summarized in Table 5.

        Table 5.  Oral LD50 values for technical isobenzan

    Species          Vehicle                        LD50        Reference
                                                 (mg/kg body

    Mouse            arachis oil                    10a,b       Worden (1969)

    Mouse            corn oil                       12.5        Spynu (1964)

    Rat              corn oil                        4.8        Howard et al. (1957)

    Rat              corn oil                       14.4        Spynu (1964)

    Rat              carboxymethyl cellulose         5.4        Stevenson (1964)

    Rat              dimethylsulfoxide               7.2        Stevenson (1964)

    Rat              arachis oil                    10b         Worden (1969)

    Rat              unknown                         8.0        Layton et al. (1987)

    Guinea-pig       arachis oil                     2.5a,b     Worden (1969)

    Golden hamster   arachis oil                    20b         Worden (1969)

    Dog              unknown                         1.6        Stevenson (1964)
    a    Average of males and females.
    b    Isobenzan 99.5%.
    7.1.2  Dermal administration

         Signs of intoxication are the same as those described for acute
    oral intoxication but they develop more slowly (Brown  et al.,
    1962). The LD50 values are summarized in Table 6.

    Table 6. Dermal LD50 values for technical isobenzan

    Species        Vehicle             LD50                Reference
                                       (mg/kg body

    Rat            arachis oil         occluded, 4         Zavon (1961)
                                       non-occluded, 10

    Rat            corn oil            non-occluded, 8.5   Spynu (1964)

    Rat            crystalline form    occluded, 60        Stevenson (1964)
    7.1.3  Parenteral administration

         The acute toxicity of isobenzan administered parenterally is
    similar to that following oral administration (Table 7). The signs
    of intoxication are similar to those observed after acute oral
    toxicity but develop more rapidly, starting less than 1 h after the
    injection (Brown  et al., 1962; Worden, 1969).

    Table 7. Parenteral LD50 values for technical isobenzan

    Route               Species    Vehicle                  LD50         Reference
                                                         (mg/kg body

    Intraperitoneal     mouse      xylene emulsion          8.2          Stevenson (1964)

    Intraperitoneal     mouse      methoxytriglycol         6.0          Cole & Casida (1986)

    Intraperitoneal     rat        dimethylsulfoxide        3.6          Stevenson (1964)

    Subcutaneous        rat,       arachis oil              6-10         Worden (1969)

    Intravenous         rat        unknown                  1.7          Zavon (1961)
    7.1.4  Formulated material

         A 50% wettable powder formulation and a 15% emulsifiable
    concentrate (in mixed petroleum xylenes) were tested for their acute
    oral toxicity to rats, mice, rabbits, hamsters, cats, and dogs. The
    LD50 values, when expressed as active material, were comparable
    with those of isobenzan itself (Stevenson, 1964; Worden, 1969). The
    dermal LD50 value for the 15% emulsifiable concentrate was
    25-35 mg isobenzan/kg body weight for Hooded-Lister rats and 6 mg
    isobenzan/kg body weight for New Zealand white rabbits, whereas in
    the case of the 50% wettable powder the LD50 was 41 mg
    isobenzan/kg body weight for rabbits (Stevenson, 1964). Rabbits
    exposed dermally to the 15% emulsifiable concentrate formulation
    behaved differently to rats similarly exposed. The rabbits generally
    lost weight due to anorexia and a failure to drink, and they would
    then convulse, even as much as 3 weeks after the exposure. However,
    if feeding and drinking were resumed quickly, the rabbits did not
    convulse (Brown, 1963, 1964).

    7.1.5  Metabolites

         The acute oral and intravenous toxicities of the metabolite
    isobenzan lactone for mice were 30 times lower than those of
    isobenzan. The oral and intravenous LD50 values were 306 mg/kg
    body weight and > 100 mg/kg body weight, respectively (Korte,

    7.2  Short-term exposure

         The short-term, long-term, and reproduction studies that were
    used for establishing a no-observed-effect level are summarized in
    Table 8.

    7.2.1  Oral administration  Mouse

         In a study by Brown  et al. (1962), groups of five male and
    five female Carworth Farm No. 1 mice were fed diets containing
    isobenzan (98%) at levels of 1, 2, 3, 4, or 5 mg/kg for up to 3
    weeks. No mortality was observed at 1 mg/kg, but at the higher
    concentrations the mortality was dose related, reaching 100% at
    5 mg/kg diet.  Rat

         Groups of eight male and eight female Carworth Farm rats were
    intubated with isobenzan (98%) in dimethylsulfoxide (0.25, 1, or
    2.5 mg/kg body weight per day) 5 days/week for 2 weeks. All rats
    dosed with 2.5 mg/kg body weight died within 5 days. All the females
    and two of the males dosed with 1 mg/kg body weight died after 5-7
    doses, whereas only one female dosed with 0.25 mg/kg body weight
    died after five doses. Weight loss preceded the death of the animals
    at the highest dose, this being the result of reduced food intake.
    No gross or microscopic changes were found in the rats dying from
    intoxication or in the survivors sacrificed 14 days after the last
    treatment (no details were reported concerning the parameters
    studied) (Brown  et al., 1962).

         In a study by Howard  et al. (1957), groups of 10 male and 10
    female Sprague-Dawley rats were fed diets containing 0, 2.5, 12.5,
    or 25 mg isobenzan/kg diet for 30 days. One female in the
    highest-dose group died. Some of the rats fed with levels of 12.5 or
    25 mg/kg were nervous and irritable, and the reduced body weight
    gain in both these groups correlated with diminished food
    consumption. At autopsy, there were some areas of necrosis of heart
    cells and haemorrhages in the heart muscle of animals fed with
    levels of 12.5 or 25 mg/kg diet.

    Table 8.  Short- and long-term oral exposure to isobenzan

    Animal (strain)          Exposure period       NOAELa           LOAELa                              References
                                                 (mg/kg diet)    (mg/kgdiet)

    Rat (Sprague-Dawley)     30 days             2.5 (0.12)     12.5 (0.62): irritability,              Howard et al. (1957)
                                                                decreased body weight gain,
                                                                histopathology changes in heart

    Dog (Beagle)             2 years             (0.08)         (0.125): convulsion, mortality          Brown & Richardson (1964)

    Dog (Scottish terrier)   2 years             (0.025)        (0.1): decreased body weight gain,      Worden (1969)
                                                                increased liver weight

    Rat (Hooded-Lister)      2 years             5 (0.25)       17.5 (0.87): convulsions                Worden (1969)

    Reproduction study

    Rat (Carworth Farm)      one generation      0.1 (0.005)    1 (0.05): decreased survival of pups    Chambers (1962a,b)
                             (2 litters)           (pups)       5 (0.25): convulsions
                                                 1.0 (0.05)

    a  Figures in parentheses are values for exposure concentration in mg/kg body weight.

         In a study by Worden (1969), groups of five male and five
    female Hooded-Lister rats were fed diets containing isobenzan
    (99.5%) (25, 35, 50, or 100 mg/kg diet) as a 15% emulsifiable
    concentrate (in mixed petroleum xylenes). After 37 days on the test
    diets, half of the surviving animals of each group were transferred
    to a control diet, while the remainder continued on the test diets
    for a further 42 days. During the first period, all rats fed with
    100 mg/kg diet died except for one male. One male and two females
    fed with 50 mg/kg diet died as did three females fed with 35 mg/kg
    diet. There were no further deaths among the rats after dosing was
    discontinued. During the second period of feeding with the test
    diet, one female fed at the lowest level died. In one rat only, a
    female fed with 50 mg/kg, the classical signs of organochlorine
    intoxication were seen in the liver. These have been described by
    Hodge  et al. (1967) as "enlarged centrolobular hepatic cells with
    cytoplasmic oxyphilia and somewhat increased and peripheral
    migration of the basophilic granules".  Dog

         Pairs of Beagle hounds (one male and one female) were given
    daily oral doses of 0, 0.08, 0.125, or 0.2 mg isobenzan (98%)/kg
    body weight in olive oil in gelatin capsules for 2 years. The dogs
    given the two highest doses had several convulsive episodes during
    the course of the study. When a dog exhibited a convulsion, dosing
    was discontinued for 8 weeks. The male dog dosed with 0.125 mg/kg
    died one week after a third convulsive episode, which followed a
    sudden fall in body weight. No signs of intoxication were observed
    in the dogs dosed with 0.08 mg/kg body weight. During this study,
    blood isobenzan concentrations were measured regularly, in
    particular at the time of convulsions. Concentrations in muscle
    tissue were determined 3 days after the convulsion, and the results
    are given in Table 9. The blood concentrations in the dogs receiving
    0.08 mg/kg body weight for 2 years without convulsions indicated
    that a plateau was reached after a relatively short exposure. The
    mean concentration was approximately 0.02 mg isobenzan/litre and the
    maximum concentration 0.04-0.05 mg/litre. The two highest doses
    caused convulsions (Brown & Richardson, 1964).

         Groups of three male and three female Scottish terriers (2.5-9
    kg body weight) received daily gavage doses of isobenzan (0, 0.025,
    or 0.1 mg/kg body weight) as 15% emulsifiable concentrate (in mixed
    petroleum xylenes) for 2 years. No deaths and no signs of
    intoxication resulted from the isobenzan administration. Body weight
    gain, urinalysis, and haematological and clinical chemistry values
    for the dogs fed with 0.025 mg/kg body weight were comparable with
    those of the control animals. At a dose level of 0.1 mg/kg body
    weight, a decrease in body weight gain, a slight increase in serum

    Table 9.  Concentration of isobenzan in the blood and muscle of dogs

    Dose (mg/kg    Sex       Number of        Blood concentration      Muscle tissue
    body weight)             convulsions      at time of convulsion    (mg/kg wet
                                              (mg/litre)               weight)

    0.08           male      none              0.04 (maximum 

                   female    none              0.05 (maximum 

    0.125          male      first two              0.06
                             third (death)          0.11               16

                   female    4                    0.03-0.06            0.18
    0.2            male      9                    0.02-0.11            0.36

                   female    6                    0.07-0.08            0.68
    alkaline phosphatase values during the second year, and an increase
    in liver weight were noted. No evidence of histopathological lesions
    attributable to isobenzan was found at either treatment level. The
    no-observed-effect level resulting from this study was 0.025 mg/kg
    body weight (Worden, 1969). The distribution of isobenzan in the
    tissues examined is summarized in section 6.2.2.

    7.2.2  Dermal administration

         When groups of five female albino rabbits were given daily
    applications of isobenzan in corn oil (0, 5, 10, 20, 30, or 40 mg
    per rabbit) to the shaven skin for 3 weeks, mortality was high at
    all dose levels, reaching 100% after 2 weeks for rabbits given doses
    of 30 or 40 mg. Histopathological examination revealed necrosis of
    the heart muscle, non-dose-related lesions of the liver, and
    degenerative changes in cells of the central nervous system in a few
    animals (Howard  et al., 1957).

    7.2.3  Intraperitoneal administration

         Groups of five male and five female Carworth Farm rats were
    injected intraperitoneally with isobenzan (98%) in
    dimethyl-sulfoxide (0.25, 1, or 2 mg/kg body weight per day) 5
    days/week for 2 weeks. All rats given the lowest dose survived, but

    two rats of each sex given 1 mg/kg and five males and four females
    given 2 mg/kg died after 5-10 doses. No gross or microscopic lesions
    were found in fatally intoxicated rats or in the survivors killed
    7-14 days after the last treatment (no details concerning
    parameters studied were reported) (Brown  et al., 1962).

    7.3  Long-term exposure

    7.3.1  Rat

         Groups of 25 male and 25 female Hooded-Lister rats were fed, at
    dietary concentrations of 5, 17.5, or 30 mg/kg (equivalent to 0.25,
    0.875, or 1.5 mg/kg body weight), isobenzan as a 15% emulsifiable
    concentrate (in mixed petroleum xylenes) for 2 years. Three control
    groups, each consisting of 25 male and 25 female rats, were used.
    Additional groups of rats, fed at the same dose levels and
    accompanied by separate control groups, were used for liver and
    kidney function tests after 20, 66, and 104 weeks. Five females fed
    at the highest dose level died during the first 3 weeks of the
    study. Signs of intoxication (such as ruffled coat, lethargy,
    muscular twitches, and mild to violent convulsions) were observed in
    animals given 17.5 or 30 mg/kg diet, mainly during the first few
    weeks. There were no adverse effects on body weight gain, food
    conversion ratios, haematological parameters, serum alkaline
    phosphatase, serum glutamic-pyruvic transaminase, total serum
    protein, or albumin/globulin ratios. Absolute liver weight was
    increased in the animals given the highest dose level. Gross and
    microscopic examinations did not reveal any compound-related
    changes, with the possible exception of thyroid hyperplasia recorded
    in four males and six females at a level of 30 mg/kg diet. The liver
    function test (bromsulfophthalein) and kidney function test (phenol
    red) showed no deviations from control values. No significant
    increase in the number and type of tumours was found. The
    no-observed-effect level for toxicological effects was 5 mg
    isobenzan/kg diet (equivalent to 0.25 mg/kg body weight) for 2 years
    (Worden, 1969).

    7.4  Skin irritation

         In a study by Worden (1969), four male guinea-pigs received a
    single application (2 mg/kg body weight) of isobenzan (99.5%) as a
    0.2% w/v solution in arachis oil to the shaved skin. The material
    was not removed from the skin. The animals were kept under
    observation for 21 days, but no irritation was observed.

         Two male and two female rabbits were given 12 successive daily
    applications (0.5 mg/kg body weight) of isobenzan (99.5%) and six
    female rats received 30 successive daily applications (0.3 mg/kg

    body weight) of isobenzan as a 0.2% w/v solution in arachis oil to
    the shaved skin. The material was left on the skin and the
    observation period was 21 days after the last application. No
    irritation was observed (Worden, 1969).

    7.5  Reproductive toxicity, embryotoxicity, and teratogenicity

         No studies on the potential teratogenicity of isobenzan have
    been reported.

    7.5.1  Mouse

         In a range-finding test, groups of 25 male and 25 female BALB/C
    mice were fed diets containing 0, 1, 2.5, 5, or 10 mg isobenzan
    (94%)/kg. The mice in the 5- and 10-mg/kg dose groups all died
    within 64 and 24 days, respectively. Only 20% of those in the
    2.5-mg/kg group survived for 120 days. The 1 mg/kg group survived
    and reproduced normally (no further data were reported). In the main
    study, groups of 108 mice of each sex of Swiss strain BALB/C were
    fed control diet and 106 mice of each sex were fed 1 mg isobenzan/kg
    diet for 30 days, after which they were randomly paired and
    continued on the same diet for 90 days. The number of litters
    produced, litter size, sex ratio, and mortality were recorded in
    this one-generation reproduction study. There were no statistically
    significant differences between the control and isobenzan-treated
    animals for any of the parameters measured (Ware & Good, 1967).

    7.5.2  Rat

         A one-generation, 2-litter reproduction study was carried out
    with groups of 20 male and 20 female weanling Carworth Farm rats
    that were fed diets containing isobenzan at levels of 0, 0.1, 1, 5,
    or 10 mg/kg for 100 days and then mated. Convulsions were seen
    during the mating period and pregnancy in females fed 10 mg/kg, and
    during the lactation period in one female fed 5 mg/kg. Pups of the
    second mating from both these treatment groups were also seen to
    convulse. Mean litter size and survival of pups were markedly
    reduced in the 10-mg/kg group and, to a lesser extent, in the
    5-mg/kg group. No clinical signs were observed in the 1-mg/kg group.
    At this dose level, the mean litter size was comparable with
    controls, but survival of the pups at 21 days was decreased. No
    effects attributable to isobenzan were found in the 0.1-mg/kg group
    (Chambers, 1962a,b).

    7.5.3  Dog

         During a 2-year study (section, three litters were
    born to a female Beagle hound dosed daily with 0.08 mg isobenzan/kg
    body weight five days per week. A male Beagle dog, dosed at the same
    level, was sire for several of the litters. The first litter
    consisted of one male and one female, both normal, and one

    still-born male. Fifteen days after birth, the female pup began to
    convulse, having only fed on the mother's milk (which contained
    0.7 mg isobenzan/litre) and at 17 days the pup was sacrificed. 
    Concentrations of isobenzan in tissues are given in section 6.2.2. 
    Two further litters of pups were born to the original dam (two male
    pups in the first litter and two pups of each sex in the second).
    These animals all appeared normal and healthy and showed no ill
    effects from the ingestion of maternal milk. One litter of pups, one
    male and one female, was born to a female Beagle dog fed 0.125 mg/kg
    body weight per day for two years. These pups did not exhibit any
    signs of intoxication and were killed when 26 days old. Autopsy did
    not reveal any structural changes. It did not appear that isobenzan
    interfered with either the male or female reproduction function
    (Brown & Richardson, 1964).

    7.6  Mutagenicity and related end-points

         No information on mutagenicity is available.

    7.7  Carcinogenicity

         No adequate carcinogenicity studies have been reported.

    7.7.1  Mouse

         Groups of 18 male and 18 female mice of two hybrid strains (the
    F1 hybrids C57Bl/6 x C3H/Anf and C57Bl/6 x AKR) were given the
    maximum tolerated dose of isobenzan in 0.5% gelatin (0.215 mg/kg
    body weight) daily from 7 to 28 days of age by stomach tube.
    Thereafter the isobenzan was mixed in the diet to a concentration of
    0.646 mg/kg, and the mice were killed at 18 months of age. No
    significant increase in tumour incidence was found (Innes  et al.,

    7.7.2  Rat

         In a long-term feeding study on rats (section 7.4.1), no
    evidence of carcinogenicity was found as a result of feeding diets
    containing up to 30 mg isobenzan/kg for 2 years (Worden, 1969).

    7.8  Special studies

    7.8.1  Biochemical studies

         Mehrotra  et al. (1982) studied the comparative effects of
    cyclodiene compounds on different ATPase activities in beef and rat
    brain synaptosomal fractions in vitro. Isobenzan significantly
    inhibited Na+-K+-ATPase in rat brain synaptosomes. A
    dose-related response was observed at up to 80 µmol/litre, but no
    increase in inhibition was observed with a further increase in the

    concentration of the compound. Oligomycin-sensitive Mg2+-ATPase in
    rat brain synaptosomes was significantly inhibited by isobenzan, a
    maximum of 64% inhibition occurring at 120 µmol/litre. In addition,
    the oligomycin-insensitive Mg2+-ATPase in rat brain synaptosomes
    was inhibited, and the inhibition was concentration dependent.
    Isobenzan did not have any effect on K+-stimulated
     p-nitrophenylphosphatase, an enzyme which is known to represent
    the dephosphorylation step in the overall reaction of the
    Na+-K+-ATPase. Oligomycin-sensitive Mg2+-ATPase in beef heart
    mitochondria was significantly inhibited.

         Isobenzan did not affect the activity of adenylate cyclase or
    phosphodiesterase in Sprague-Dawley rat brain synaptosomes  in vitro
    at concentrations of up to 200 µmol/litre (Kodavanti  et al.,

         Several studies into the effect of isobenzan on the transfer of
    ammonia in brain have indicated that isobenzan acts by increasing
    brain ammonia levels before and during convulsions. Glutamic acid,
    glutamine, and alpha-ketoglutaric acid, which are utilized in an
    ammonia-binding mechanism, become overwhelmed, resulting in free
    ammonia accumulating in the cerebral tissues (Hathway & Mallinson,
    1964; Hathway, 1965; Hathway  et al., 1965).

    7.8.2 Neurotoxicity

          In vitro studies using fresh rat brain synaptic membranes
    showed isobenzan to be a potent inhibitor of the binding of the
    convulsant  tert-butylbicyclophosphorothionate (TBPS) to
    brain-specific sites, thereby indicating an action at the
    gamma-aminobutyric acid (GABA)-regulated chloride channel. Metabolic
    activation by rat liver microsomes did not enhance the potency for
    inhibition. This inhibition indicates that isobenzan binds to the
    same site as TBPS, suggesting that isobenzan acts in a manner
    similar to non-competitive GABA-A antagonists and providing a basis
    for its convulsant action in mammals (Lawrence & Casida, 1984).

         Bloomquist  et al. (1986) produced a concentration-dependent
    inhibition of 36Cl uptake into mouse brain vesicles by adding
    isobenzan to mouse brain homogenate. The inhibitory activity was
    confined to that portion of 36Cl uptake that was GABA dependent. 
    The insecticide concentration producing 50% inhibition (I50) of
    36Cl uptake was 2.0 (0.83 to 5.1) µmol/litre, and the inhibitory
    potency (I50) value for 35S-TBPS binding in rat brain
    synaptosomes was 0.30 µmol/litre (Lawrence & Casida, 1984).

         Cole & Casida (1986) confirmed in a study with male
    Swiss-Webster mice administered isobenzan intraperitoneally that a
    correlation also exist  in vivo between binding to mouse brain GABA
    receptors and convulsive activity. The inhibitory potency (IC50)

    for  in vitro TBPS binding to mouse brain synaptosomes is
    0.03 µmol/litre. It was shown that the inhibitory potencies of
    cyclodienes, including isobenzan, parallel their acute oral
    toxicities. Isobenzan was slightly more potent than endrin and
    produced virtually complete inhibition of GABA-dependent chloride
    uptake at 30 µmol/litre. There was a significant linear correlation
    between the 36Cl flux and 35S-TBPS-binding assays.

    7.8.3  Pharmacological studies

         Pharmacological studies on the function of organ systems in
    various animal species (such as rats, guinea-pigs, rabbits, cats,
    and frogs) after the administration of isobenzan by different routes
    showed that the only significant effect was a disturbance of the
    central nervous system associated with convulsions. This effect was
    due to stimulation of the higher brain centres at the level of the
    medulla and above. Changes in respiratory rate, heart rate, and
    salivary secretion were probably mediated by the central nervous
    system as a secondary effect of central nervous stimulation.
    Barbiturates were found to control these convulsions. The
    stimulation of brain activity was reflected in the occurrence of
    electroencephalographic changes in the pre-convulsive stage and
    during the convulsive episodes. This corresponds to the situation in
    cases of human intoxication by occupational exposure to cyclodiene
    insecticides as described by Hoogendam  et al. (1962, 1965) and
    Chambers (1962c).

         Ibrahim (1964) showed that isobenzan injected intraperitoneally
    at a toxic dose (7 mg/kg body weight) into male Wistar rats produced
    a higher tension of contraction in the gastrocnemius muscle at lower
    frequencies of stimulation than in controls. The maximum tetanic
    tension was also attained at a lower frequency.  An increase in the
    duration of the "active state" of the muscle was considered to be
    the most like explanation.


    8.1  General population exposure

         No poisoning incidents or untoward effects of long-term
    exposure of the general population have been reported.

    8.2  Occupational exposure

         Isobenzan was initially manufactured and handled in the
    Netherlands between 1958 and 1965. Aldrin, dieldrin, and endrin were
    also produced in the same manufacturing plant and, consequently, in
    many cases the exposure was mixed. Routine medical examination of
    233 workers, who were exposed for more than 4 years and who followed
    normal procedures during that period, did not reveal any
    abnormalities in EEG, clinical chemistry or haematological
    parameters, or liver microsomal enzyme induction (Jager, 1970;
    Versteeg & Jager, 1973). The mean isobenzan concentration in the
    blood of 20 operators after cessation of exposure decreased from
    22 µg/litre in 1965 to 7 µg/litre in 1969. The biological half-life
    of isobenzan in the blood (at the state of equilibrium of isobenzan
    in body tissues) was estimated to be of the order of 2.8 years
    (Jager, 1970).

         In the 7 years of isobenzan production, 15 cases of clinical
    intoxication, including eight cases with convulsions, were reported.
    The mean concentration of isobenzan in the blood of nine workers at
    the time of intoxication was 23 µg/litre, the range being
    17-30 µg/litre. Although these workers recovered fully, it took
    longer than with the related cyclodiene insecticides. In three
    cases, certain typical complaints, such as headache, dizziness,
    drowsiness, and irritability, persisted for 6 months, and the return
    to normal of the modified EEG pattern sometimes took more than a
    year. In one case of acute over-exposure, without signs of
    intoxication, the blood isobenzan concentration decreased from
    8 µg/litre to less than 2 µg/litre within 3 days (Jager, 1970).

         The data from plant workers indicated a threshold level of
    isobenzan in blood below which no signs or symptoms of intoxication
    occur. This level was found to be 15 µg/litre (Jager, 1970).

         Ribbens (1985) carried out a mortality study on the
    above-mentioned industrial workers exposed to aldrin, dieldrin,
    endrin, and isobenzan. Vital status and cause of death were assessed
    for 232 of the total population of more than 1000 workers. This
    group was selected for follow-up on account of the high degree of
    exposure in the initial years of manufacturing and formulation and
    the long exposure (mean 11 years) and observation (mean 24 years)
    periods. Total observed mortality was 25 as opposed to 38 expected

    on the basis of death statistics for the male Dutch population. Of
    the nine cancer deaths, three were caused by lung cancer, while the
    remaining six were each of a different nature.  The author concluded
    that although exposures in this group were high and exposure as well
    as observation periods long, this study did not reveal any
    indication of a specific carcinogenic activity of these pesticides.


    9.1  Microorganisms

         In laboratory studies, sandy loam soil was treated with 250 or
    2500 mg isobenzan/kg (concentrations that exceeded the recommended
    rates). At both concentrations, the carbon dioxide production was
    inhibited to almost the same extent (21 and 24%, respectively)
    during a 30-day test period. The addition of glucose to the soil
    reduced the inhibitory effect to 5 and 4%, respectively. Isobenzan
    at 250 mg/kg did not influence nitrification in the soil up to 18
    days after treatment (Bartha  et al., 1967).

         Screening studies on microorganisms in pure culture were
    carried out on nutrient agar plates with isobenzan either
    incorporated in a uniformly emulsified form (1000 mg/kg) or as a
    thin surface film (1 mg/cm2). The growth of the gram-positive
     Bacillus megaterium was inhibited, but not that of various
    gram-negative organisms such as several  Pseudomonas strains,
     Escherichia coli, Klebsiella aerogenes W5, or  Achromobacter
     butyri (Trudgill & Widdus, 1970).

    9.2  Aquatic organisms

         Groups of five adult Harlequin fish  (Rasbora heteromorpha)
    were exposed for 2 h at a temperature of 20 °C to water (pH 7.2)
    containing isobenzan (99%), dissolved in DMSO, at a concentration of
    0.01, 0.1, or 1 mg/litre. The fish were then transferred to clean
    water and observed for an additional 48 h. The treatment with
    1 mg/litre caused disorientation and the fish became excited by
    external stimuli, lost the ability to swim, and, finally, all died
    within 1 h. In some cases, they appeared to convulse. Isobenzan at
    0.1 mg/litre caused similar symptoms; within 2 h of exposure, all
    five fish died. No fish died at 0.01 mg/litre, but slight changes in
    swimming behaviour were observed (Brown  et al., 1962). When
    guppies  (Poecilia reticulata) were tested in the same way, the
    symptoms of intoxication and susceptibility were similar to those in
    Harlequin fish, but the guppies were slower to react (Brown et al.,

         Data on the acute toxicity of isobenzan for aquatic organisms
    in flow-through tests are given in Table 10.

    Table 10.  Acute toxicity of isobenzan (technical grade, 94%) for aquatic organisms

    Organism            Developmental   Temperature   Parameter     Concentration    Reference
                        stage           (°C)                        (µg/litre)

    Brown shrimp        juvenile        17            48-h EC50     0.034a           US EPA
    (Penaeus                                                                         (1987)

    Eastern oyster      juvenile        18            96-h EC50     32b              US EPA
    (Crassostrea                                                                     (1987)

    Sheepshead minnow   juvenile        17            48-h LC50     2.0a             US EPA
    (Cyprinodon                                                                      (1987)

    Spot                juvenile        13            48-h LC50     0.32c            US EPA
    (Leiostomus                                                                      (1987)

    a    Salinity 30 ng/litre.
    b    Salinity 33 ng/litre.
    c    Salinity 22 ng/litre.
    9.3  Terrestrial organisms

    9.3.1  Soil invertebrates

         In laboratory studies, plain-field sand was treated once with
    0.05 mg isobenzan/kg and stored at 13 or 24 °C. The springtail
     (Folsomia candida) was used for bioassays lasting up to 16 weeks. 
    The biological activity of isobenzan persisted slightly longer at
    the higher temperature, killing 100% of the insects after 16 weeks
    (Thompson, 1973).

    9.3.2  Birds  Acute toxicity

         Isobenzan (> 99%) is highly toxic to birds when administered
    as a single oral dose (Table 11). LD50 values range from
    1-10 mg/kg.  Short-term toxicity

         When groups of five male and five female Japanese quail
     (Coturnix coturnix japonica) were fed diets containing 2 or 10 mg
    isobenzan/kg, the mean survival time in the high-dose group was 6.9
    days (range, 2-20 days). The residues in the liver and brain
    averaged 3.4 mg/kg and 1.4 mg/kg, respectively. In the low-dose
    group, the mean survival time was 45.9 days (range, 19-65 days) and
    the average residues in liver and brain were 6 mg/kg and 1.6 mg/kg,
    respectively. The concentration of isobenzan in the liver of birds
    fed 2 mg/kg was significantly higher than that in the high-dose
    group, but the concentration in the brain showed no difference
    (Koeman, 1971).

    Table 11. Oral LD50 values of isobenzan for birds

    Species                         LD50 (mg/kg       Reference
                                    body weight)

    Mallard duck (female)           4.15              Hudson et al. (1984)
    (Anas platyrhynchos)            (2.47-6.97)

    Coturnix quail (female)         4.2               Schafer & Brunton (1979)
    (Coturnix coturnix)

    Grackle                         1.3               Schafer & Brunton (1979)
    (Quiscalus quiscula)

    Pigeon                          10                Schafer & Brunton (1979)
    (Columba livia)

    Red-winged blackbird (male)     3.2               Schafer & Brunton (1979)
    (Agelaius phoeniceus)

    Sparrow                         1                 Schafer & Brunton (1979)
    (Passer domesticus)

    Starling                        2.4               Schafer & Brunton (1979)
    (Sturnus vulgaris)
         When groups of 20 Rhode Island Red laying hens were fed
    isobenzan (15% emulsifiable concentrate) at levels of 0.1, 0.25,
    0.75, or 1 mg/kg diet for 14 weeks, no effects were seen on food
    consumption, egg production, egg weight, or egg fertility (Verma
     et al., 1967).

    9.4  Population and ecosystem effects

    9.4.1  Soil microorganisms

         In a sugar cane field in India, Srivastava (1966) studied the
    effect of isobenzan (1 kg/ha) on nitrification of ammonium sulfate
    in the soil. The insecticide-treated soil contained higher amounts
    of total inorganic nitrogen and ammonium nitrogen (80% increase) up
    to 60 days after treatment than did untreated soil samples,
    indicating impaired nitrification.

    9.4.2  Soil invertebrates

         In a study by Kelsey & Arlidge (1968), five sandy loam plots of
    pasture in New Zealand were treated with Telodrin (15% emulsifiable
    concentrate) at a rate of 2 kg isobenzan/ha in June 1962. The
    populations of all recorded groups (grass grub, porina, Collembola,
    Diptera, Hemiptera, Coleoptera, mites, and earthworms), except
    nematodes, were drastically reduced. There was no recovery in the
    populations of any of the affected groups during the period up to
    October 1965. In silt loam plots treated with isobenzan granules
    (1 kg/ha) in April 1964, the populations of Coleoptera, Collembola,
    Diptera, mites, and earthworms were all reduced, but to a lesser
    extent than in the test using 2 kg/ha. However, grass grub and
    Hemiptera were not significantly affected, and nematode numbers were
    elevated 2 years after the treatment. Studies on root development
    showed that 90% of roots with root hairs were located within a mat
    of plant debris above the soil, whereas in controls 99% were located
    in the soil. Plant growth was retarded. The moisture content of the
    treated plots was significantly less than that of control plots,
    indicating that the capacity of soil to absorb and retain water had
    been reduced.

         When loose sandy soil in New Zealand was treated with 2.25 kg
    isobenzan/ha as 5% granules, the population reduction, 1-18 weeks
    after treatment, was 90-100% for larval Coleoptera and Lepidoptera
    and 75% for Diptera and earthworms. The number of surface
    arthropods, 5-15 days after treatment, was reduced by 45%. Six
    months after treatment, little effect was found on nematodes
    (13% reduction), bacteria (18% reduction), and fungi (7% increase)
    (Moeed, 1975).


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    formulators in the CAPSA plant in Venezuela, Sittingbourne, Shell
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    1.  Résumé et évaluation

         Autant qu'on sache, l'isobenzan, un insecticide organochloré
    n'a été fabriqué que pendant la période 1958-1965. Plusieurs années
    aprés, on puisait toujours sur les stocks existants. A l'heure
    actuelle, les seules sources importantes d'exposition sont
    vraisemblablement les sites de décharge initiaux de déchets
    industriels ou les boues de dragage provenant de sédiments

         Une fois épandu sur le sol, la majeure partie de l'isobenzan
    disparaît rapidement. Après quoi, la fraction restante se décompose
    beaucoup plus lentement. Elle persiste dans le sol de deux à sept
    ans selon la nature de celui-ci. Au laboratoire, l'isobenzan se
    décompose dans les eaux de surface en l'espace de quelques semaines
    lorsqu'il est exposé à la lumière naturelle ou artificielle.

         Le sol, les eaux souterraines et superficielles provenant des
    polders constitués de sédiments contaminés par des organochlorés,
    notamment des dérivés cyclodiéniques, contenaient encore plusieurs
    années après, de faibles résidus d'isobenzan. En 1979-1980, on n'a
    pas détecté d'isobenzan (limite de détection 0,01 mg/kg de poids
    sec) dans les sédiments des cours d'eau des Pays-Bas. Après
    traitement du sol, les résidus qui subsistent sur les récoltes sont
    généralement faibles (inférieurs à 0,05 mg/kg de végétaux), mais on
    peut en trouver des quantités plus fortes sur certaines racines
    (jusqu'à 0,2 mg/kg dans les carottes). Des enquêtes de type "panier
    de la ménagère" effectuées lorsqu'on utilisait de l'isobenzan en
    agriculture, n'ont pas permis de déceler de résidus dans les denrées
    contrôlées (moins de 0,01 mg/kg).

         Chaque fois qu'on a laissé paître des bovins dans des pâturages
    traités par de l'isobenzan, on a constaté que les produits laitiers
    obtenus contenaient des résidus de cet insecticide. C'est ainsi que
    dans deux échantillons de beurre, on a trouvé 0,07 et 0,15 mg
    d'isobenzan par kg de produit, les concentrations dans le lait
    entier allant de 0,005 à 0,07 mg/kg. Le lait en poudre n'en
    contenait toutefois que 0,005 mg/kg. Lors du traitement industriel
    des produits laitiers, plus de 50% du résidu disparaît selon le type
    de traitement.

         On ne dispose d'aucune donnée sur les quantités d'isobenzan
    présentes dans le sang ou les tissus adipeux de la population
    générale. Des travailleurs exposés à l'isobenzan lors de la
    fabrication ou de la formulation de cet insecticide, présentaient
    des taux sanguins (sang total) allant jusqu'à 0,041 mg/litre. Dans
    les échantillons de sang total prélevés sur des personnes vivant à
    proximité d'une unité de production, la concentration d'isobenzan
    était inférieure à la limite de détection (0,001 mg/litre).

         L'isobenzan est facilement résorbé par la paroi du tube
    digestif et il passe dans le sang sans modification. Il se forme des
    métabolites hydrophiles et notamment une lactone. L'isobenzan
    s'accumule dans les tissus et les organes des rats et des chiens
    selon l'ordre: graisses > foie = muscle > cerveau > sang. Les
    concentrations tissulaires chez les rattes sont généralement plus
    faibles que chez les rats, spécialement dans les graisses. La
    demi-vie biologique dans le tissu adipeux était ainsi de 10,9 jours
    chez les rats et de 16,6 jours chez les rattes. Chez un chiot
    femelle dont le sang contenait 0,09 mg d'isobenzan par litre, on a
    observé des convulsions 15 jours après la naissance. L'animal
    n'avait été nourri qu'avec le lait de sa mère, une chienne Beagle à
    qui l'on avait fait absorber de l'isobenzan et dont le lait en
    contenait 0,7 mg/litre. Des effets analogues sur les petits ont été
    observés lors d'une étude de reproduction sur le rat. Chez la vache,
    l'isobenzan est excrété dans le lait.

         Les larves de moustiques et les champignons terricoles
    métabolisent l'isobenzan de la même manière que les vertébrés,
    notamment sous forme de lactone. L'isobenzan est très persistant
    dans l'environnement et s'accumule dans les organismes vivants. Il
    est extrêmement toxique pour les poissons, les crevettes et les
    oiseaux. Aux Pays-Bas, pays où l'on fabriquait l'isobenzan, on a
    trouvé des résidus dans des oeufs de sternes vivant sur la côte
    hollandaise qui atteignaient 0,45 mg/kg (moyenne, 0,09 mg/kg). Dans
    les moules et le poisson, les résidus moyens étaient de 0,05 mg/kg
    en 1965. Dans les parcelles traitées par de l'isobenzan à raison de
    2 kg/ha, on a constaté une réduction du nombre de lombrics. Il y
    avait réduction de la nitrification avec accroissement corrélatif de
    l'azote minéral dans les sols traités par l'isobenzan à raison
    d'1 kg/ha; en revanche, les études en laboratoire n'ont mis en
    évidence aucun effet sur la nitrification à des doses correspondant
    à 250 g/ha.

         L'isobenzan présente une forte toxicité aiguë pour les
    mammifères, que ce soit par la voie orale ou par la voie percutanée.
    Le mode d'action de l'isobenzan consiste en une stimulation
    excessive du système nerveaux central conduisant à des convulsions.
    La toxicité aiguë des diverses formulations d'isobenzan correspond à
    la proportion de matière active.

         L'isobenzan n'est pas irritant pour la peau mais certaines de
    ses formulations peuvent l'être.

         Des études limitées à court et à long terme, au cours
    desquelles on a administré par voie orale de l'isobenzan à des
    souris, à des rats et à des chiens, ont montré que ce composé
    pouvait induire des lésions histologiques au niveau du foie, du type
    de celles qu'on observe classiquement avec les organochlorés. Une
    étude de longue durée sur des rats a permis de déterminer que la

    dose sans effet observable était de 5 mg/kg de nourriture (soit
    l'équivalent de 0,25 mg/kg de poids corporel). Chez le chien, la
    dose sans effet nocif observable, déterminée à la suite d'une étude
    de deux ans, était de 0,025 mg/kg de poids corporel. 

         Une étude de reproduction portant sur une génération de rats a
    montré que la dose sans effet nocif observable était de 0,1 mg/kg de
    nourriture (soit l'équivalent de 0,05 mg/kg de poids corporel. A la
    dose de 1 mg/kg de nourriture (soit l'équivalent de 0,05 mg/kg de
    poids corporel), il y a eu réduction de la survie des ratons.

         Aucune étude de tératogénicité ni de mutagénicité n'a été

         Une étude de deux ans sur des rats (administration par voie
    orale) et une étude sur des souris n'ont pas permis de mettre en
    évidence un pouvoir cancérogène quelconque, mais ces études
    n'étaient pas adaptées à une telle évaluation.

         La base de données toxicologiques sur l'isobenzan est
    incomplète. En général on estime que, d'après les critères actuels,
    les données sont d'une qualité médiocre et sont en tous cas
    insuffisantes pour permettre une évaluation du risque que ce composé
    présente pour la santé humaine ou l'environnement. 

         Les données concernant l'exposition humaine se limitent à des
    études effectuées sur des travailleurs d'une usine hollandaise qui
    étaient employés à la fabrication et à la formulation d'isobenzan et
    d'insecticides cyclodiéniques apparentés. Aucun cas d'irritation
    cutanée n'a été signalé. Dans plusieurs cas d'intoxication, on a
    observé des convulsions mais les anomalies du tracé
    électro-encéphalographique étaient réversibles. Le seuil limite
    d'intoxication (pour les convulsions), a été estimé à 0,015 mg
    d'isobenzan par litre de sang et la demi-vie biologique de ce
    composé dans le sang humain est, semble-t-il, de l'ordre de 2,8

    2.  Conclusions et recommandations

         L'isobenzan est extrêmement toxique et très persistant. Les
    données dont on dispose sur le danger qu'il représente sont
    incomplètes mais néanmoins suffisantes pour montrer que ce danger
    est réel pour les personnes qui le manipulent ainsi que pour
    l'environnement, de sorte qu'il faut éviter toute contamination
    humaine ou environnementale qui résulterait de l'utilisation de ce
    produit comme insecticide ou autre.


    1.  Resumen y evaluación

         Según los datos de que se dispone, el isobenzano, un
    insecticida organoclorado, sólo se fabricó durante el periodo
    1958-1965. Durante los años siguientes se utilizaron las existencias
    almacenadas. En la actualidad, se cree que las únicas fuentes
    importantes de exposición son los lugares donde originalmente se
    evacuaron los desechos industriales o los materiales dragados de
    sedimentos contaminados.

         Cuando se aplica el isobenzano al suelo, se produce una rápida
    pérdida inicial; después, el resto del compuesto se degrada mucho
    más despacio. Persiste en el suelo durante 2 a 7 años, según el tipo
    de suelo. En condiciones de laboratorio, el isobenzano se descompone
    en las aguas de superficie en pocas semanas cuando se expone a la
    luz natural o artificial.

         El suelo, las aguas subterráneas y las aguas superficiales de
    pólders construidos con sedimentos contaminados por sustancias
    organocloradas, inclusive compuestos de ciclodieno clorado, aún
    contenían pequeños residuos de isobenzano algunos años después. En
    1979-1980, no se detectó isobenzano (límite de detección: 0,01 mg/kg
    de peso seco) en el sedimento de ríos de los Países Bajos. Tras el
    tratamiento del suelo, los residuos en las cosechas suelen ser bajos
    (menos de 0,05 mg/kg de cosecha), pero pueden encontrarse
    concentraciones superiores en algunos tubérculos (hasta 0,2 mg/kg en
    zanahorias). En las encuestas de mercado realizadas durante la época
    de uso agrícola del isobenzano no se detectaron residuos en los
    alimentos analizados (menos de 0,01 mg/kg).

         En los productos lácteos procedentes de ganado que se alimentó
    en pastos tratados con isobenzano se encontraron residuos del
    insecticida. Dos muestras de mantequilla contenían 0,07 y 0,15 mg de
    isobenzano/kg de producto, mientras que los niveles en la leche
    entera fueron de 0,005 mg/kg a 0,07 mg/kg. En la leche deshidratada,
    no obstante, se encontraron sólo 0,005 mg/kg. Durante la elaboración
    de los productos lácteos se perdía hasta el 50% del residuo, según
    el tipo de tratamiento.

         No se dispone de datos sobre los niveles de isobenzano en la
    sangre o el tejido adiposo de la población general. Los operarios
    expuestos al isobenzano en las plantas de fabricación y elaboración
    presentaron niveles medios en sangre entera de hasta 0,041 mg/litro.
    En muestras de sangre entera procedente de personas que vivían en
    las proximidades de una de las plantas, la concentración de
    isobenzano estaba por debajo del límite de detección
    (0,001 mg/litro).

         El isobenzano es absorbido rápidamente a través de la pared
    gastrointestinal y es transportado por la sangre sin alteraciones.
    Se forman metabolitos hidrófìlos de los que se ha identificado uno,
    la lactona de isobenzano. El isobenzano se acumula en los tejidos y
    los órganos de ratas y perros en el orden siguiente: grasa > hígado
    = músculo > cerebro > sangre. Las concentraciones tisulares en las
    hembras de rata son en general superiores a las que aparecen en los
    machos, sobre todo en la grasa. En la rata se determinó que la
    semivida biológica en la grasa del organismo es de 10,9 días en los
    machos y 16,6 días en las hembras. En un cachorro hembra de perro,
    cuya sangre contenía 0,09 mg de isobenzano/litro, se observaron
    convulsiones a los 15 días del nacimiento. El cachorro sólo se había
    alimentado de leche de su madre, una Beagle a la que se había
    administrado isobenzano y cuya leche contenía 0,7 mg/litro. En un
    estudio de reproducción en ratas se observaron efectos similares en
    las crías. Las vacas excretan isobenzano con la leche.

         Las larvas de mosquito y los hongos del suelo metabolizan el
    isobenzano del mismo modo que los vertebrados, dando lactona de
    isobenzano como metabolito.

         El isobenzano es muy persistente en el medio ambiente y se
    bioacumula. Es sumamente tóxico para los peces, los camarones y las
    aves. En los Países Bajos, país en el que se fabricaba el
    isobenzano, los residuos encontrados en los huevos de golondrinas de
    mar de las costas holandesas ascendieron a 0,45 mg/kg (promedio:
    0,09 mg/kg), mientras que el promedio de residuos encontrados en
    mejillones y peces fue de 0,05 mg/kg en 1965. Se observó una
    disminución del número de lombrices en terrenos tratados con
    isobenzano a razón de 2 kg/ha. Se redujo la nitrificación, con el
    consiguiente aumento del nitrógeno inorgánico, en los suelos
    tratados con isobenzano sobre el terreno a razón de 1 kg/ha, si bien
    en estudios de laboratorio no se demostró efecto alguno en la
    nitrificación con dosis equivalentes a 250 g/ha.

         La toxicidad aguda del isobenzano para los mamíferos es elevada
    por las vías oral y percutánea. La forma de acción de su toxicidad
    es la sobreestimulación del sistema nervioso central, que da lugar a
    convulsiones. La toxicidad aguda de las preparaciones de isobenzano
    refleja el porcentaje de ingrediente activo presente.

         Aunque el isobenzano no irrita la piel, algunos productos
    preparados a partir de él pueden causar irritación.

         En estudios limitados a corto y largo plazo de administración
    oral realizados en ratones, ratas y perros se ha demostrado que el
    isobenzano puede provocar en el hígado cambios histológicos que
    reponden al tipo clásico de intoxicación por compuestos
    organo-clorados. En un estudio realizado a largo plazo en ratas, se
    determinó un nivel efectos sin observados de 5 mg/kg de dieta

    (equivalente a 0,25 mg/kg de peso corporal), y en un estudio en
    perros de dos años de duración se determinó un nivel sin observación
    de efectos adversos de 0,025 mg/kg de peso corporal.

         En un estudio de reproducción en una generación de ratas se
    obtuvo un nivel sin efectos adversos observados de 0,1 mg/kg de
    dieta (equivalente a 0,05 mg/kg de peso corporal). Con un nivel de
    1 mg/kg de dieta (equivalente a 0,05 mg/kg de peso corporal)
    disminuyó la supervivencia de las crías.

         No se han comunicado estudios sobre la teratogenicidad ni la
    mutagenicidad del compuesto.

         No se observó potencial carcinogénico en un estudio de
    administración oral a ratas durante dos años ni en un estudio de
    administración oral a ratones, pero esos estudios no eran apropiados
    para evaluar la carcinogenicidad.

         La base de datos toxicológicos correspondiente al isobenzano es
    incompleta. En general, actualmente se considera que la calidad de
    los datos es mediocre e insuficiente para evaluar los riesgos que
    representa para la salud humana o el medio ambiente.

         Los datos sobre personas expuestas se limitan a estudios
    realizados en trabajadores de una fábrica de los Países Bajos
    durante la fabricación y la elaboración de preparaciones de
    isobenzano y otros insecticidas de ciclodieno clorado afines. No se
    comunicaron casos de irritación cutánea. En varios casos de
    intoxicación, se produjeron convulsiones pero los cambios del
    trazado electroencefalográfico resultaron ser reversibles. El nivel
    umbral de intoxicación (en el caso de las convulsiones) se estimó en
    0,015 mg de isobenzano/litro de sangre, y se calculó que la semivida
    biológica del isobenzano en la sangre humana es del orden de 2,8

    2.  Conclusiones y recomendaciones

         El isobenzano es sumamente tóxico y muy persistente. La
    información de que se dispone sobre los riegos del isobenzano es
    incompleta, pero, aún así, basta para indicar que el riesgo que
    supone para los que lo manipulan y para el medio ambiente es tan
    elevado que no debería permitirse la exposición humana o del medio
    ambiente a esta sustancia, ya sea utilizada como insecticida o para
    cualquier otro fin.

    See Also:
       Toxicological Abbreviations
       Isobenzan (HSG 61, 1991)