WHO/FOOD ADD./69.35



    Issued jointly by FAO and WHO

    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Working Party of Experts and the WHO Expert
    Committee on Pesticide Residues, which met in Geneva, 9-16 December,



    Geneva, 1969



    Chemical names

         isopropyl-2-hydroxy-2,2-di(p-chlorophenyl) acetate;

         isopropyl 4,4'-dichlorobenzilate (IUPAC)


         Acaralata(R), Rospin(R), Gesakar(R), Chlormite(R)

    Structural formula


    Other information on identity and properties

    The technical material is a yellowish crystalline preparation with a
    purity of approximately 95 per cent. No data have been submitted on
    the composition of the technical product.


    Biochemical aspects

    When carbon14 labelled chloropropylate was administered orally to
    pairs of male and female rats at about 1.6 mg/kg the radioactivity was
    excreted in the urine and faeces. No radio-active carbon dioxide was
    expired. The excretion pattern of the radioactivity differed between
    the two sexes, the male voiding 75 per cent of the dose in the
    faeces, and six per cent in the urine, and the female 49 per cent in
    the faeces and 31 per cent in the urine. Most of the radioactivity
    was eliminated in the first 48 hours. The total tissue residue of
    radioactivity 120 hours after administration was 0.9 per cent and 1.0
    per cent in the male and female respectively. The majority of these
    residues were in the liver and fat (Cassidy et al., 1968).

    Metabolic studies extending over 10 days were performed on pairs of
    dogs (one male and one female) treated orally with technical
    chloropropylate at 12.8 or 64.1 mg/kg on five consecutive days.
    Urinary excretion accounted for 5.2 and and 33.2 per cent of the

    total dose in the urine of the males at low and high dose levels, the
    corresponding figures for the female being 3.2 and 33.7 per cent. In
    the faeces, 6.4 and 3.4 per cent were detected in the male, at low and
    high doses respectively, and 16.9 and 7.3 per cent in the female. No
    residues were detected in blood, brain, fat, liver, kidney or muscle
    at sacrifice. The method of analysis employed would not detect
    dichlorobenzilic acid conjugates. (Hazleton Laboratories, Inc., 1964)
    The presence of the probable metabolite, dichlorobenzilic acid has
    been demonstrated in dog urine, by thin layer chromatography (Mattson
    et al., 1965).

    Acute toxicity (active ingredient) (oral)
    Animal   Route   Formulation or solvent     LD50 mg/kg   Reference

    Mouse    Oral    20 per cent suspension       >5 000     Stenger, 1962
                     in gum arabic

    Rat      Oral    20 per cent suspension       >5 000     Stenger, 1963a
                     on gum arabic

    Rat      Oral    40 per cent wettable        >13 840     Ind. Bio-Test,
                     powder                                  1965a

    Rat      Oral    25 per cent emulsifiable      5 000     Ind. Bio-Test,
                     solution                                1965b

    Fowl     Oral    25 per cent emulsifiable      2 500     Sanderson, 1963

    Short-term studies

    Avian wildlife

    No deaths resulted when mallard ducks were fed diets containing 0.8
    per cent chloropropylate for seven days, although reduced food
    consumption and body-weight occurred at this dose level (Woodard
    Research Corp, 1966a).

    Bobwhite quail were fed for seven days on diets containing 0.8, 0.4
    and 0.2 per cent chloropropylate. The LD50 was about 0.4 per cent
    and reduced food intake and weight loss were apparent in all groups.
    (Woodard Research Corp., 1966b)


    Groups of five male and five female rats dosed orally by intubation
    six times weekly for four weeks with 50, 250 or 500 mg/kg/day
    chloropropylate suspended in gum arabic failed to show any toxic
    effects as judged by changes in survival, body-weight gain and
    microscopic examination of tissues after autopsy (Geigy, 1964).

    Administration over 12 weeks of 0, 100, 1000, 5000 and 25 000 ppm of
    chloropropylate in the diet to groups of 21 male and 21 female rats
    resulted in a mortality of 29 per cent at the 5000 ppm level and 70
    per cent at the 25 000 ppm level. At the highest level, hair loss
    occurred after two weeks, and bloody nasal discharge was frequently
    observed. Body-weight gain was doubtfully depressed in males at 1000
    ppm and definitely depressed in both sexes at higher dose levels. Food
    intake levels were reduced in both sexes at 25 000 ppm.
    Histopathological examination of tissues revealed dose related changes
    in the liver, and an increasing incidence of testicular atrophy at
    doses of 1000 ppm and above. (Stenger, 1963b)


    Administration over three months of 0, 100, 500 or 3000 ppm of
    chloropropylate in a dry diet to groups of three male and three female
    dogs resulted in slight depression of average bodyweight gain in male
    dogs at 3000 ppm. Haematology, biochemical studies, urinalysis, gross
    and histopathology were all comparable to controls. Organ to
    body-weight ratios were increased in the case of liver and kidney at
    3000 ppm in both sexes (Hazleton Laboratories, Inc., 1965).

    A one-year interim report of a two-year feeding study using
    chloropropylate 40 per cent wettable formulation in groups of three
    male and three female dogs at 0, 100, 500 and 3000 ppm active
    ingredient indicates some depression of female growth rate in two out
    of three female dogs at 500 ppm. At 3000 ppm, body-weight loss or
    insufficient gain (five out of six) gastric stress and trauma (five
    out of six), elevated alkaline phosphatase (four out of four, day 90),
    and mortality (three out of six) occurred. The survivors were reduced
    to an intake of 2000 ppm after 104 days and were taken off the test at
    the one-hundred-and-sixteenth day. They were again dosed with 2000 ppm
    from the one-hundred-and-ninety-eighth day of the study. After one
    year, this 2000 ppm group showed no adverse effect, except slightly
    high urinary albumin in one male and one female animal (Industrial
    Bio-Test Laboratories 1967).

    Long-term studies


    Three groups of 30 male and 30 female rats were fed 0, 40, or 125 ppm
    active ingredient as the 50 per cent wettable formulation in the diet
    for two years. The majority of the parameters, including mortality,

    body-weight, food intake, haematology and incidence of neoplasms were
    comparable to the controls. However, at 125 ppm the decrease in
    prostate weight, apparent already as a trend at 40 ppm, became
    significant. Similarly an increased incidence of chronic renal
    disease, and doubtful fatty changes in the liver were more commonly
    encountered at 125 ppm (Woodard, 1966c).

    Special studies

    (a) Reproduction

    In a three-generation study, three groups of 10 male and 20 female
    rats were fed 0, 25 or 50 ppm of chloropropylate in their diet. The
    litters from the second matings were used to provide the new
    generations. The F1b litter did not receive the test diet until 28
    days after weaning, but it is not stated whether there was a similar
    delay period in the case of the F2b litter. The F0 animals showed no
    toxic effects as measured by changes in body-weight, mortality or
    reproductive capacity. Litters from treated groups were comparable to
    the controls in numbers of litters per group, litter size, mean birth
    weight, mean weanling weights, and survival to weaning. Abnormalities
    were within normal limits. Histopathology of the F3b weanling rats
    indicated a slightly higher frequency of hepatic cell vacuolization,
    and mineralization of renal tubules than that encountered in the
    controls but such pathological abnormalities are frequently
    encountered in normal rats (Woodard, 1966-67).

    (b) Studies on the metabolite

    Dichlorbenzilic acid, was fed to groups of 20 male and 20 female rats
    for 99 days at dose levels of 0, 20, 100, 500 and 2500 ppm active
    ingredient in a 20 per cent powder. Food consumption body-weight
    gain, mortality, organ weights and gross and histopathology showed no
    significant changes from the controls. A tendency to slight depression
    of kidney and testes weight was noted at 2500 ppm (Domenjoz, 1965).


    In one report of the two 12-week rat studies, the body-weight data for
    the males show a dose-related decrease throughout the study. It is
    improbable that the lower dose levels reduce body-weight

    In the rat three-generation study, the data indicate that there was a
    delay between weaning and starting the animals on the test-diet, in
    the case of one litter. The reason for this delay and the extent of it
    are not specified. Such a delay period could affect the maturation of
    the reproductive organs and, consequently, fertility data in this
    study are of little value. There is no evidence of teratogenic
    activity, although detailed skeletal or soft tissue examinations have
    not been made.

    In the interim report of the dog study, the female body-weight gain is
    apparently depressed in two out of the three dogs at 500 ppm. No such
    depression is apparent following return to dietary level of 2000 ppm
    after temporary discontinuation of the 3000 ppm and so this apparent
    depression of body-weight gain may be an artifact. It should, however,
    be borne in mind: (1) that a tolerance may have developed in the
    animals receiving the high dose following this earlier exposure, and
    (2) that the rate of growth would be less in one-year old dogs than in
    the much younger dogs exposed at the initiation of the study.

    Attention is drawn to the presence of chronic renal disease in the rat
    two-year study, and to the increased urinary albumen in two dogs at
    the top dose level. Furthermore, there is the possibility of
    metabolites of unknown toxicity being formed.


    Level causing no significant toxicological effects

         Rat: 40 ppm equivalent to 2 mg/kg body-weight per day.

    Estimate of temporary acceptable daily intake for man

         0-0.01 mg/kg body weight.


    Use pattern

    Pre-harvest treatments

    Chloropropylate is used in several countries as a contact acaracide
    for the control of mites on apples, pears, stone fruit, citrus fruit,
    soft fruit, grapes, olives, vegetables, tea and cotton.

    The recommended rates of application range from 20 to 60 g/100 l, and
    the amount of spray liquid applied is generally 500-1000 l/ha for
    low-grown crops (vegetables, etc.) and 2000-2500 l/ha for high-grown
    crops (e.g. fruit orchards). (US Dept. of Agric., 1967)

    Post-harvest treatments

    No post-harvest treatment is recommended.

    Other uses

    No other uses are recommended.

    Residues resulting from supervised trials

    Residue data are available from supervised trials on several food
    crops, grown under various conditions, using various rates of

    application and pro-harvest intervals (Geigy, 1963 and 1968) These
    data refer to apples and pears, stone fruit (apricots, peaches, plums,
    prunes), citrus fruit (oranges, lemons), small fruit (strawberries,
    blueberries), vegetables (tomatoes, muskmelons, cucumbers). In most
    cases normal dosage rates were applied in accordance with label
    recommendations; in a few experiments higher dosages were included.
    The residues were analysed with a GLC method using microcoulometric
    detection, sensitive to 0.05 ppm. Results of supervised trials and
    available information on application mainly refer to work in the
    United States of America. From other countries only few relevant data
    are available. The following table presents a summary of typical
    residue data:

                     Rate of                   Post-treatment     Residue
                   application    Number of       interval       whole fruit
                    (g/100 l)     treatments       (days)        basis (ppm)

    Apples           25               1               1             1.2
                     25               1              21             0.9
                     50               1               1             2.0
                     50               1              21             1.3
                      1.12 kg*        1               1             3.2
                      1.12 kg*        1              21             1.5
                      2.24 kg*        1               1             4.6
                      2.24 kg*        1              21             3.6

    Pears             0.28 kg*        1               1             0.8
                      0.28 kg*        1               7             0.1
                      1.12 kg*        1               7             0.6

    Grapefruit       30               1               1             2.1**
                     30               1              21             1.2**
                     90               1               1            12.5**
                     90               1              21             6.1**

    Oranges          30               1               1             0.6**
                     30               1              21             0.7**
                     90               1               1             1.0**
                     90               1              21             0.9**

    Tomatoes          0.56 kg*        1               3             0.1
                      0.56 kg*        1              14             0.05 max.
                      2.24 kg*        1               3             0.12
                      2.24 kg*        1              14             0.09

                     Rate of                   Post-treatment     Residue
                   application    Number of       interval       whole fruit
                    (g/100 l)     treatments       (days)        basis (ppm)
    Cantaloupes       2.24 kg*        1               1             0.22
                      2.24 kg*        1              14             0.07

    *  Rate application/ha.
    ** Residue in peel : pulp after seven days was <0.1.
    Fate of residues

    General comments

    Chloropropylate can be considered as a persistent compound. More
    information is needed on the nature of terminal residues in plants,
    animals and their products.

    In soils

    No information available.

    In plants

    Experiments have been performed to examine if and to what extent
    breakdown products derived from chloropropylate could be found, with
    particular reference to the possible occurrence of
    4,4'-dichlorobenzilic acid.

    Apple trees were sprayed with 2 lb/100 gal; samples were taken three,
    14 and 21 days after the application. The sensitivity of the
    analytical method was 0.1 ppm. In recovery studies it was shown that
    4,4'-dichlorobenzilic acid could be detected without interference by
    chloropropylate. It appeared from this study that chloropropylate is
    found mainly on the outer surface of the treated apples. No unchanged
    chloropropylate could be detected in the pulp. None of the treated
    apples contained detectable amounts of 4,4'-dichlorobenzilic acid
    (Murphy et al., 1966).

    In animals

    No information available other than that referring to special
    toxicological and biochemical work.

    In storage and processing

    No data are available on the fate of residues during storage and
    processing. Since the residue remains mainly on the skin and migrates
    only to a very small extent or not at all into the pulp, it may be

    expected that washing and peeling of treated fruit will remove most of
    the residue. No data are available on the effects of cooking.

    Evidence of residues in food, in commerce or at consumption

    Food moving in commerce

    No information available.

    Food at the time of consumption

    No information available.

    Methods of residue analysis

    See chlorobenzilate.

    National tolerances

         Country                 Crop             Tolerance (ppm)

    United States of America     Apples, pears    5

    (United States of America Federal Register)



    Chloropropylate is a persistent and specific acaracide with biological
    properties related to those of chlorobenzilate. The compound, although
    registered for use in a relatively large number of countries, does not
    seem to be extensively applied. No information was available on the
    extent of use of this compound. Furthermore, the total composition of
    the technical material has not been furnished. The limited residue
    data which have been made available are mainly based upon experiments
    in the United States of America and Switzerland. Residue data from
    other countries are desired. No data have been furnished on the level
    of residues in food moving in commerce, and on the rate of
    disappearance during storage and processing.

    In certain cases, e.g. grapes and blueberries, recommendations for
    tolerances cannot be made until further data are available on the
    possible carry-over of the residue in wine, and the necessity for the
    utilization of the compound on blueberries. No information is
    available on the nature of the terminal residues in plants and animal

    A referee method of analysis has not been established. However,
    gas-liquid chromatography appears suitable for this purpose, but must
    be further developed by collaborative studies. Comparative evaluation
    of the different detectors used in gas chromatographic methods, and
    evaluation of the different methods of extraction are needed.


    Temporary tolerances

    The following temporary tolerances (to be in effect until 1972) are to
    apply to raw agricultural products moving in commerce unless otherwise
    indicated. In the case of fruits and vegetables the tolerances should
    be applied as soon as practicable after harvest and in any event prior
    to actual retail to the public. In the case of commodities entering
    international trade, the tolerances should be applied by the importing
    country at the point of entry or as soon as practicable thereafter.
    The figures refer to the parent compound only.

         Apples, pears, citrus (on whole-fruit basis)   -3.0 ppm
         Tomatoes, cantaloupes                          -1.0 ppm

    Further work or information

    Required before 30 June 1972:

    1. Information on the composition of the technical product.

    2. Information on the nature of terminal residues in plants, animals,
       and their products.

    3. Data on the extent of use in various countries.

    4. Data from countries other than the United States of America and
       Switzerland on the required rates and frequencies of application,
       pre-harvest intervals, and the resultant residues.

    5. Data on residue levels in raw agricultural products moving in

    6. Data on the disappearance of residues during storage and

    7. Data on the possible carry-over of residues into wine as a result
       of the treatment of grapes.

    8. Comparative evaluation of the different detectors used in
       gas-liquid chromatographic methods and of different methods of
       extraction for regulatory purposes.

    9. Identification of metabolites other than dichlorobenzilic acid and
       investigation of their toxicology.

    10. Adequate reproduction studies in the rat or other species.

    11. Further investigation of kidney function and excretion.


    Collaborative studies to establish a referee method.


    Cassidy, J. E., Min, B. and Murphy, R. T. (1968) Metabolic fate of
    C14 chloropropylate, in white rats. A balance study. Geigy Chemical
    Corp. Unpublished report

    Domenjoz, R. (1965) Dichlorbenzilsäure Toxizität bei chronischer 
    Verabreichung. Institute of Pharmacology, Rheinische
    Friedrich-Wilhelm's University, Bonn, Unpublished report

    Geigy S.A., J.R. (1963) Chlorpropylat im Vergleich zu Chlorbenzilat.
    Unpublished report

    Geigy. (1964) Toxicology of chloropropylate (G24163). Geigy Chemical 
    Corp., unpublished report

    Geigy S.A., J.R. (1968) Chloropropylate working paper. Unpublished  

    Hazleton Laboratories Inc. (1964) Method development for the analysis
    of chloropropylate and chlorobenzilate in biological fluids and tissue
    specimens. Metabolic distribution and excretion of chloropropylate and
    chlorobenzilate in dogs, Unpublished report

    Hazleton Laboratories Inc. (1965) Three-month dietary administration.
    Dogs. Final report. Chloropropylate 50W, Unpublished report

    Industrial Bio-Test Laboratories. (1965a) Acute toxicity studies on 
    chloropropylate 40W, Unpublished report

    Industrial Bio-Test Laboratories. (1965b) Acute toxicity studies on
    chloropropylate 25E, Unpublished report

    Industrial Bio-Test Laboratories. (1967) Two-year chronic oral
    toxicity of chloropropylate 40W. Beagle dogs. Twelve-month status
    report, Unpublished report

    Mattson, A. M., Beaudoin, R. L. and Schneller, J. (1965) Comparison of
    urinary metabolites in dogs after administration of chlorobenzilate or
    chloropropylate. Geigy Chemical Corp., Unpublished report

    Murphy, R., Kahrs, R. and Mattson, A. M. (1966) Dissipation of
    residues of chlorobenzilate and chloropropylate on apples. Analytical
    Department of Geigy Research Laboratories, Division of Geigy Chem.
    Corp., Ardsley, New York, Unpublished report

    Sanderson, D. M. (1953) The avian toxicity of chloropropylate.
    Chesterford Park Research Station. Fisons Pest Control Ltd.,
    Unpublished report

    Stenger. (1962) Chlorpropylat (G24163). Akute Toxizität - Maus per os. 
    Geigy Chemical Corp., Unpublished report

    Stenger. (1963) G24163 (Chlorpropylat). Akute Toxizität - Ratte per
    os. Geigy Chemical Corp., Unpublished report

    Stenger. (1963b) G24103 (Chlorpropylat). Subchronische toxizität
    - Ratte. Geigy Chemical Corp., Unpublished report

    United States of America Federal Register 27, F.R. 12092, pav. 120-218

    United States of America Department of Agriculture. (1967) Summary of  
    registered pesticide chemical uses, 30 September

    Woodard. (1966a) Chloropropylate. Subacute toxicity in mallard ducks,
    Unpublished report, Woodard Research Corp.

    Woodard. (1966b) Chloropropylate. Safety evaluation on fish and wild 
    life (Bobwhite quail, rainbow trout, bluegill sunfish and goldfish),
    Unpublished report, Woodard Research Corp.

    Woodard. (1966c) Chloropropylate. Safety evaluation by dietary feeding
    to rats for 104 weeks, Unpublished report, Woodard Research Corp.

    Woodard. (1966-67) Chloropropylate. Three generation reproduction
    study in the rat. Histological report addenda, Unpublished report,
    Woodard Research Corp.

    See Also:
       Toxicological Abbreviations
       Chloropropylate (WHO Pesticide Residues Series 2)