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    FAO Meeting Report No. PL/1965/10/1
    WHO/Food Add./27.65

    EVALUATION OF THE TOXICITY OF PESTICIDE RESIDUES IN FOOD

    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Committee on Pesticides in Agriculture and
    the WHO Expert Committee on Pesticide Residues, which met in Rome,
    15-22 March 19651

    Food and Agriculture Organization of the United Nations
    World Health Organization
    1965

                
    1 Report of the second joint meeting of the FAO Committee on
    Pesticides in Agriculture and the WHO Expert Committee on Pesticide
    Residues, FAO Meeting Report No. PL/1965/10; WHO/Food Add./26.65

    ALDRIN

    Chemical name

         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.

    Synonyms

         HHDN, Octalene

    Empirical formula

         C12H8Cl6

    Structural formula

    CHEMICAL STRUCTURE 

    BIOLOGICAL DATA

    Biochemical aspects

         Following the feeding of aldrin to animals it is stored in the
    tissues, especially in the fat (Bann et al., 1956; 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)
    (Lehman, 1956), but this storage ratio decreases rapidly to less than
    one with an intake of 50 ppm.

         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 (Morsdorf et al.,
    1963).

    Acute toxicity

                                                                        
    Animal             Route      LD50 mg/kg      Reference
                                  body-weight
                                                                        
    Mouse              Oral           44          Borgmann et al., 1952
                                                  Council of Europe, 1962

    Rat, male          Oral          38-54        Borgmann et al., 1952
                                                  Council of Europe, 1962
                                                  Gaines, 1960
                                                  Lehman, 1951
                                                  Treon & Cleveland, 1955

    Rat, female        Oral          46-67        Borgmann et al., 1952
                                                  Council of Europe, 1962
                                                  Gaines, 1960
                                                  Lehman, 1951
                                                  Treon & Cleveland, 1955

    Rat, female     Intravenous       18          Council of Europe, 1962

    Guinea-pig         Oral           33          Borgmann et al., 1952
                                                  Council of Europe, 1962

    Rabbit             Oral          50-80        Borgmann et al., 1952
                                                  Council of Europe, 1962
                                                  Treon & Cleveland, 1955

    Dog                Oral          65-95        Borgmann et al., 1952
                                                  Council of Europe, 1962
                                                                        

         Man. A 23-year-old man intentionally drank 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.

         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 25 female rats were fed diets 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).

         Groups of 5 animals of each were given 2.5, 5, 25, 75 or 300 ppm
    of either 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 was increased 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 of aldrin 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. 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 50, 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 on the experimental studies reported

         The primary mode of action of aldrin is on the central nervous
    system. This is the mechanism of death in acute poisoning. Symptoms of
    central nervous system 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 rats.

         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 as compared to the controls, but the liver was not
    particularly affected. Liver tumours were, however, significantly
    increased on a dosage of 10 ppm in one strain of mice susceptible to
    the development of these tumours.

         In rats, it has been suggested (Fitzhugh et al., 1964) that the
    apparent tumorigenic properties of aldrin could be related to a
    general type of effect.

    EVALUATION

    Level causing no significant toxicological effect

         In the rat and the dog a no-effect level has not been
    demonstrated.

    Acceptable daily intake for man

         From the data presented, an acceptable daily intake for man
    cannot be estimated. Until further evidence is forthcoming, every
    effort should be made to see that the intake of aldrin for man is kept
    at the lowest possible level.

    Further work required

         Additional long-term toxicity studies in other species than the
    rat, including further reproduction studies. Determination of a
    no-effect level in more than one species.

    REFERENCES

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

    Bann, J. M. et al. (1956) J. Agr. Food Chem., 4, 937

    Borgmann, A. R. et al. (1952) Kettering Lab., University of
    Cincinnati Report, March.

    Council of Europe (1962) Agricultural pesticides, Strasbourg

    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.
    Toxic., 2, 551

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

    Ivey, M. C. et al. (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., 11, 378

    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

    Morsdorf, K. et al. (1963) Med. Exp., 8, 90

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

    Street, J. C. et al. (1957) Proc. West. Sec. Amer. Soc. Anim.
    Prod.,44 (1)

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

    Treon, J. F. et al. (1951) Unpublished report from Kettering Lab.,
    University of Cincinnati

    Treon, J. F. et al. (1955) Kettering Lab., University of Cincinnati
    Report, February
    


    See Also:
       Toxicological Abbreviations
       Aldrin (ICSC)
       Aldrin (PIM 573)
       Aldrin (FAO/PL:CP/15)
       Aldrin (FAO/PL:1967/M/11/1)
       Aldrin  (IARC Summary & Evaluation, Supplement7, 1987)
       Aldrin (IARC Summary & Evaluation, Volume 5, 1974)