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    FAO, PL:CP/15
    WHO/Food Add./67.32

    EVALUATION OF SOME PESTICIDE RESIDUES IN FOOD

    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Working Party and the WHO Expert Committee on
    Pesticide Residues, which met in Geneva, 14-21 November 1966.1

             
    1 Report of a Joint Meeting of the FAO Working Party and the WHO
    Expert Committee on Pesticide Residues, FAO Agricultural Studies, in
    press; Wld Hlth Org. techn. Rep. Ser., 1967, in press

    ALDRIN

    IDENTITY

    Synonyms

    HHDN, Octalene(R)

    Explanation

    Aldrin is a technical product containing at least 95 per cent of HHDN
    of which the composition is as follows:

    1,2,3,4,10,10-hexachloro-1,4,4a,5,8,8a-hexahydro-endo-1,4-exo-5,8-
    dimethanonaphthalene;
    1,2,3,4,10,10-hexachloro-1,4,4a,5,8,8a-hexahydro-exo-1,4-endo-5,8-
    dimethanonaphthalene.

    Formula

    CHEMICAL STRUCTURE 

    DATA AND TOXICOLOGICAL EVALUATION

    Biochemical aspects

    When 14C-aldrin was applied to growing cultures of Aspergillus and
    Penicillium species, dieldrin and more hydrophilic metabolites were
    found in the culture medium and in the mycelium. Mosquito larvae
    (Aedes aegypti) cultivated in an aqueous medium to which
    14C-aldrin is added, can convert this compound to hydrophilic
    metabolites (Ludwig et al., 1966).

    Following the feeding of aldrin to animals it is stored in the
    tissues, especially in the fat (Bann et al., 1966; Ivey et al., 1961;
    Lehman, 1956; Street et al., 1957; Treon & Cleveland, 1955). At low
    levels of intake (1 ppm) the storage ratio is large (about 60 times)
    but this ratio decreases rapidly to less than one with an intake of 50
    ppm (Lehman, 1956).

    The aldrin content of the blood plasma of men occupationally exposed
    for 259-6044 hours over a period of eight years ranged between 0.0007
    and 0.0023 ppm and was directly proportional to the duration of

    exposure. Aldrin added to human serum could be only partially
    recovered, probably because of in vitro interaction or binding with
    some constituent of serum such as lipoproteins. The plasma of an adult
    male about 18 hours after ingestion of aldrin and 10 hours after the
    last convulsion contained 0.036 ppm aldrin and 0.279 dieldrin. Twenty
    days later these concentrations were 0.0018 and 0.090 ppm respectively
    (Dale et al., 1966).

    Aldrin is largely and readily converted in the animal body, especially
    in the liver, to dieldrin (Bann et al., 1956; Ivey et al., 1961; Treon
    & Cleveland, 1955). The rate of change has not been fully established,
    and is independent of the site of entrance into the body. The dieldrin
    is stored without further change and may be recovered as such from
    animal products and tissues, including the eggs of fowls and the milk
    of dairy cows within 24 hours after ingestion (Bann et al., 1956).
    Fifteen minutes after an intravenous injection of 14C-aldrin, aldrin
    and its metabolites were found in the bile (Mörsdorf et al., 1963).

    In vitro epoxidation by rat liver microsomes was found to be about
    10 times greater in males than in females (Wong & Terriere, 1965).
    Rats were fed 1 and 25 ppm of aldrin for 120 days; two metabolites
    were found in the urine, one of which was much more abundant in males
    than in females (Datta et al., 1965).

    Experiments with rats showed that 14C-aldrin given intravenously was
    converted in 24 hours mainly into hydrophilic metabolites. After 48
    hours the presence of these metabolites could be demonstrated in most
    organs and tissues. In the urine of rabbits given 14C-aldrin
    intravenously, the main metabolite could be identified as one of the
    two enantiomorphs of 6,7-trans-dihydroxy-dihydroaldrin. The oral
    LD50 of this compound in mice is 1250 mg/kg bodyweight, and the
    intravenous LD50 is 51 mg/kg body-weight. It was found that after
    intravenous injection of labelled aldrin in rats, radioactive products
    could be demonstrated in the bile within one hour. In 4 hours, 16.2
    per cent of the radioactivity was excreted in the bile. Most of the
    radioactivity was in the form of hydrophilic products. Perfusion tests
    on rat livers showed conversion of aldrin into dieldrin. From these
    results it was concluded that the conversion of the insecticide does
    in fact take place in the animal organism (Ludwig et al., 1966).

    Studies in rats with 14C-aldrin have shown that with daily
    administration of a constant dose of aldrin (4.3 µg per animal,
    calculated to be equivalent to 0.2 ppm in the diet) a saturation
    equilibrium is reached after a certain time (in male rats after about
    50 days; whereas in females this saturation equilibrium is reached
    after as long as 200 days). After discontinuation of the daily oral
    administration, the compound had a biological half-life period of
    10-11 days in male rats and 100 days in female rats. In faeces and
    urine, 70 and 95 per cent respectively of the radioactivity was in the
    form of hydrophilic metabolites. The conversion and excretion rate in
    female rats was lower at the same dose levels than in the male rats.
    The radioactivity found in the tissues of female animals was about
    double that found in male rats. Remarkable differences in the

    concentration of metabolites in lung, liver, spleen and kidney were
    found; in the female rats, the content of hydrophilic metabolites was
    lower and the dieldrin content higher than in the males (Ludwig et
    al., 1966).

    Acute toxicity
                                                                                          
    Animal               Route         LD50                    Reference
                                       mg/kg body-weight
                                                                                      

    Mouse                Oral          44                      Borgmann et al., 1952

    Rat, male            Oral          38-54                   Borgmann et al., 1952
                                                               Gaines, 1960
                                                               Lehman, 1951
                                                               Treon & Cleveland, 1955

    Rat, female          Oral          46-67                   Borgmann et al., 1952
                                                               Gaines, 1960
                                                               Lehman, 1951
                                                               Treon & Cleveland, 1955

    Rat, female          Intravenous   18                      Barnes, J. M., 1957

    Guinea-pig           Oral          33                      Borgmann et al., 1952

    Rabbit               Oral          50-80                   Borgmann et al., 1952
                                                               Treon & Cleveland, 1955

    Dog                  Oral          65-95                   Borgmann et al., 1952
                                                                                      
        Man A 25-year-old man intentionally ingested a quantity of aldrin
    equivalent to 25.6 mg per kg of body-weight. The following symptoms
    were noticed: generalized convulsions, E.E.G. changes, haematuria
    and albuminuria. Recovery was complete (Spiotta, 1951).

    Short-term studies

    Rat. Groups of 12 rats (6 male and 6 female) were fed diets
    containing 0.5, 2.5, 75 and 150 ppm aldrin for 90 days. The liver
    weight was increased at the two higher dosages. The mortality rate was
    increased at the 150 ppm level (Borgmann et al., 1952).

    In a feeding study lasting from 6 to 7 months, dosage levels of 5, 10
    and 25 ppm aldrin were used with groups of 5 females. No enlargement
    of the liver or other gross change was noted. Histological data are
    not described. In a 9-month feeding experiment, with 20 female rats 
    per group, the dosage levels were 5, 15, 25 and 45 ppm of aldrin. 
    There was an increase in the liver/body-weight ratio at 45 ppm 
    (Borgmann et al., 1952).

    Groups of 5 animals of each sex were given 2.5, 5, 25, 75 or 300 ppm
    of purified or technical aldrin in the diet for 26 weeks. Two rats of
    each group were killed before the end of the treatment, and the last
    three were killed before the thirty-seventh week. All the animals
    receiving 300 ppm died in 2 weeks. At 75 ppm the survival rate was
    good. Liver/body-weight ratio in males at 25 ppm and in both sexes at
    75 and 300 ppm. Swelling of centrolobular liver cells with peripheral
    distribution of the cytoplasmic granules were often seen. At 2.5 and 5
    ppm these changes were seen with the same frequency as in the
    controls. They were markedly obvious at 25 ppm and over, but regressed
    after the end of the treatment (Treon et al., 1951).

    Quail and pheasants. These animals died following concentrations of
    5 ppm in the diet (Dewitt, 1955).

    Dog When dogs were fed, for 5 or 6 days per week, diets containing
    10 to 30 ppm of aldrin, death occurred after periods of feeding
    ranging from a few days to about 7 months, Three groups of suckling
    puppies (11 days old), 3 each group comprising 2 males and 1 female
    were given 1.5, 3.0 and 4.5 mg/kg per day respectively, on 5 days per
    week. All the animals died within 38 days. A 2-month-old male and a
    female survived about 6 to 7 months when given 0.9 to 1.8 mg/kg
    body-weight per day for 6 days per week (Treon & Cleveland, 1955).

    When 3 groups of 3 dogs (both sexes) were given orally 0.2, 0.6 and
    2.0 mg of recrystallized aldrin per kg of body-weight daily for one
    year, 5 of them produced litters but the pups died early, probably
    because of high quantities of aldrin or dieldrin in the milk of the
    dams. Histological liver changes were found in the dogs (Kitselman,
    1953).

    Groups of 4 dogs (2 male and 2 female) were given 1 and 3 ppm of
    aldrin in their diet for 68 weeks. Liver damage occurred in 3 animals
    on the 3 ppm dosage level. There were significant increases in
    liver/body-weight ratios in the dogs on 3 ppm of aldrin. Kidney damage
    occurred in the female at the 1 ppm dosage level. An average
    concentration of aldrin of 0.3 ppm remained in the adipose tissue in
    the animals fed 3 ppm and 0.18 ppm remained at 1 ppm. Dieldrin
    occurred at a concentration of 25.4 ppm in the fat of a dog fed 1 ppm
    of aldrin (Treon & Cleveland, 1955; Treon et al., 1955).

    A group of 12 dogs was given aldrin orally for 2 years at the
    following daily doses - 0.2 mg/kg (2 dogs), 0.5 mg/kg (4 dogs), 1, 2
    and 5 mg/kg (2 dogs each). The animals at 5 mg/kg and one of those
    given 2 mg/kg died within 24 days. The other animal at 2 mg/kg and the
    2 given 1 mg/kg died in 1 year. All the others survived until the end
    of the experiment but for a dog at 0.5 mg/kg which died in a few days.
    Fatty changes in the liver and kidney, associated with "mild bone
    marrow changes" were observed at the highest doses. At 0.5 mg/kg one
    animal showed convulsions. No effects were seen at 0.2 mg/kg (Fitzhugh
    et al., 1964).

    Sheep and cattle. Heifers given 0.5-1 mg/kg/day for 64 days and
    cattle given 1.9 mg/kg/day for 10 days were not affected, whereas
    sheep given 6 mg/kg/day died within 28 days (Kitselman et al., 1950).

    Long-term studies

    Mouse. Groups of approximately 200 young C3HeB/Fe mice, equally
    divided by sex, were fed a diet containing 10 ppm of aldrin for their
    life-span (maximum 2 years). The aldrin shortened their average
    life-span by 2 months, as compared with an equal number of controls,
    and significantly increased the incidence of hepatic tumours (Davis &
    Fitzhugh, 1962).

    Rat. Groups of 25 female rats were fed diets containing 5, 10 and 20
    ppm of recrystallized aldrin for 64 weeks. The group on 20 ppm showed
    an increase in weight over the controls which was correlated with an
    increased food intake. At the 10 ppm and 20 ppm levels the oestrus
    cycle was disturbed (Ball et al., 1953).

    In a 2-year feeding experiment, groups of 20 rats (10 male and 10
    female) were given 5, 10, 50, 100 and 150 ppm of aldrin. The
    concentrations of 100 and 150 ppm increased the mortality rate and
    those of 10, 100 and 150 ppm produced microscopic changes in the
    liver. A single rat on 10 ppm of aldrin had specific liver changes;
    the rats on 5 ppm of aldrin had no noticeable liver changes. Aldrin
    was stored in the tissues at all dosage levels (Borgmann et al.,
    1952).

    In a second 2-year feeding experiment a group of 80 rats (40 male and
    40 female) was given 2.5, 12.5 and 25 ppm of recrystallized aldrin.
    There was a questionable increase in mortality rate at the 25 ppm
    level in females. Significant increase in the liver/body-weight ratio
    occurred in males at all levels and at 12.5 and 25 ppm in females.
    Histological liver changes characteristic of organic chlorine
    compounds occurred at all dosage levels of aldrin (Treon & Cleveland,
    1955).

    In a third 2-year feeding experiment, groups of 24 rats (12 male and
    12 female) were given 0.5, 2, 10, 50, 100 and 150 ppm of aldrin.
    Concentrations of 50 ppm and above in the diet increased the mortality
    rate in a dose-response relationship. Liver/body-weight ratio
    increased at all levels of feeding. Characteristic microscopic lesions
    occurred in the liver at all levels; these were minimal at 0.5 ppm but
    increased in severity with dosage. There was an increase in tumour
    incidence among treated animals at all feeding levels and particularly
    at lower levels, but no single type of tumour predominated (Fitzhugh &
    Nelson, 1963).

    Aldrin was fed to groups of 16 female rats at 2.5, 12.5 and 25 ppm for
    three generations; at 12.5 and 25 ppm the number of pregnancies was
    reduced. The incorporation of aldrin into the diets of lactating

    females has a "slight to moderate" effect on mortality among the
    offspring at 2.5 ppm. It was severe at higher doses (Treon &
    Cleveland, 1955).

    Comments

    The primary site of action of aldrin is the central nervous system.
    CNS stimulation is the cause of death in acute poisoning. Signs of CNS
    stimulation are also seen after repeated high doses. Repeated doses at
    lower levels give rise to liver damage and, in this respect, young
    dogs are more susceptible than older dogs.

    In one long-term feeding experiment in rats there was a general
    increase in tumour production in the experimental animals at the lower
    dosage levels an compared to the controls, but the liver was not
    particularly affected. Liver tumours were, however, significantly
    increased at a dose level of 10 ppm in one strain of mice susceptible
    to the development of these tumours.

    TOXICOLOGICAL EVALUATION

    Levels causing no toxicological effect

    Dog: Questionable effects were seen at 1 ppm in the diet, equivalent
    to 0.025 mg/kg.

    Rat: Minimal changes were produced at 0.5 ppm in the diet,
    equivalent to 0.025 mg/kg/day.

    Estimate of acceptable daily intake for man

    0-0.0001 mg/kg body-weight*

    Further work required

    Elucidation of the significance of the finding that aldrin is one of
    the compounds which affect liver cellular metabolism (p. 3).

    Development of methods of toxicological investigation aimed at
    defining and clarifying the various biological changes seen in the
    reported studies of this compound, with a view to removing doubts
    which may remain as to its safety in use.

    RESIDUES IN FOOD AND THEIR EVALUATION

    See the monograph on Dieldrin.

                 

    * Sum of aldrin and dieldrin by weight.

    REFERENCES PERTINENT TO BIOLOGICAL DATA

    Ball, W. L., Kay, K. & Sinclair, J. W. (1953) Arch. industr. Hyg.,
    7, 292

    Bann, J. M., DeCino, T. J., Earle, N. W. & Sun, Y. P. (1956) J. Agr.
    Food Chem. 4, 937

    Barnes, J. M. (1957) Unpublished report.

    Borgmann, A. R., Kitselman, C. H., Dahm, P. A. & Pankaskie, J. E.
    (1952) Unpublished report from Kettering Laboratory, University of
    Cincinnati

    Dale, W. E., Curley, A. & Cueto, C., jr (1966) Life Sciences, 5,
    47

    Datta, P. R., Laug, E. P., Watts, J. O., Klein, A. K. & Nelson, M. J.
    (1965) Nature, 208, 289

    Davis, K. J. & Fitzhugh, O. G. (1962) Toxicol. Appl. Pharmacol., 4,
    187

    Dewitt, J. B. (1955) J. Agr. Food Chem., 3, 672

    Fitzhugh, O. G. & Nelson, A. A. (1963) Unpublished data from the
    United States Food and Drug Administration

    Fitzhugh, O. G., Nelson, A. A. & Quaife, M. L. (1964) Food Cosmet.
    Toxicol., 9, 551

    Gaines, T. B. (1960) Toxicol. Appl. Pharmacol., 2, 88

    Ivey, M. C., Claborn, H. V., Mann, H. D., Radeleff, R. D. & Woodard,
    G. T. (1961), J. Agr. Food Chem., 9, 374

    Kitselman, C. H. (1953) J. Amer. vet. med. Ass., 123, 28

    Kitselman, C. H., Dahm, P. A. & Borgmann, A. R. (1950) Amer. J. vet.
    Res., 41,

    Lehman, A. J. (1951) Quart. Bull. Assoc. Food and Drug Officials
    U.S., 15, 122

    Lehman, A. J. (1956) Quart. Bull. Assoc. Food and Drug Officials
    U.S., 20, 95

    Ludwig, G., Arent, H., Kochen, W., Poonawalla, N., Rechmeier, G.,
    Stiasni, M., Vogel, J. & Korte, F. (1966) Paper presented at the
    Scientific Plant Protection Conference, Budapest, Hungary

    Mörsdorf K., Ludwig, G., Vogel, J. & Korte, F. (1963) Med. Exp.,
    8, 90

    Spiotta, E. J. (1951) Arch. industr. Hyg., 4, 560

    Street, J. C., Butcher, J. E., Raleigh, R. J. & Clanton, D. C. (1957)
    Proc. West. Sec. Amer. Soc. Anim. Prod., 46 (1)

    Treon, J. F. & Cleveland, F. P. (1955) J. Agr. Food Chem., 3, 402

    Treon, J. F., Dutra, F. R., Shaffer, F. R., Cleveland, F. P., Wagner,
    W. & Gahegan, R. (1951) Unpublished report from Kettering Laboratory,
    University of Cincinnati

    Treon, J. F. (1955) Unpublished report from Kettering Laboratory,
    University of Cincinnati

    Wong, D. T. & Terriere, L. C. (1965) Biochem. Pharmacol., 14, 375
    


    See Also:
       Toxicological Abbreviations
       Aldrin (ICSC)
       Aldrin (PIM 573)
       Aldrin (FAO Meeting Report PL/1965/10/1)
       Aldrin (FAO/PL:1967/M/11/1)
       Aldrin  (IARC Summary & Evaluation, Supplement7, 1987)
       Aldrin (IARC Summary & Evaluation, Volume 5, 1974)