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    AGP:1970/M/12/1

    WHO/FOOD ADD/71.42

    1970 EVALUATIONS OF SOME PESTICIDE RESIDUES IN FOOD

    THE MONOGRAPHS

    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
    Group on Pesticide Residues, which met in Rome, 9-16 November, 1970.

    FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS

    WORLD HEALTH ORGANIZATION

    Rome, 1971

    FENTIN COMPOUNDS

    Explanation

    At the 1965 Joint FAO/WHO Meeting on Pesticide Residues, the
    toxicology of two fentin compounds, namely fentin hydroxide
    (triphenyltin hydroxide) and fentin acetate. (triphenyltin acetate),
    was considered. The deliberations are summarized in a monograph
    entitled "Triphenyltin Compounds" (FAO/WHO, 1965). Since that meeting,
    additional information has become available on these two fentin
    compounds, as well as on fentin chloride (triphenyltin chloride).
    Because all these fentin compounds appear to react similarly in plants
    and in animals, they have been grouped together in this completely
    revised monograph

    IDENTITY

    Chemical names

         1) triphenyltin hydroxide

         2) triphenyltin acetate

         3) triphenyltin chloride

    Synonyms

         1) fentin hydroxide, Du-ter(R), (Trinicide W20)

         2) fentin acetate, Brestan(R), Hoe 2824(R)

         3) fentin chloride, Brestanol(R), Hoe 2872(R)

    Structural formulas

    CHEMICAL STRUCTURE 

    Other relevant chemical properties

    The pure fentin hydroxide is a white odourless crystalline solid, with
    a melting point of 118-120°C. Solubility in water at 20°C is 8 ppm,

    and it is moderately soluble in most organic solvents. It is stable at
    room temperature, but decomposition occurs on heating above 60°C.

    The pure fentin acetate is a white, odourless, crystalline solid, with
    a melting point of 124-125°C. Its solubility in water at 20°C is 28
    ppm, and it is of low solubility in most organic solvents.

    Fentin acetate is stable when stored under normal conditions in dry
    air. At 90°C, no decomposition can be detected; at 150°C, 15 percent
    decomposes within three hours. In the presence of water, the acetate
    is almost completely hydrolysed within eight hours at 20°C.

    The pure fentin chloride is a white crystalline solid, with melting
    point at 106°C. Its solubility in water is 40 ppm. It is stable when
    stored in the dark in dry air. In the presence of water it hydrolyses
    into the hydroxide.

    Purity

    The technical products are usually of the following purities:

         fentin hydroxide    : 95 percent
         fentin acetate      : 94 percent
         fentin chloride     : 94 percent

    The impurities consist mainly of diphenyltin compounds and
    tetraphenyltin.

    This report is based on the data obtained with the fentin compounds
    manufactured in Germany (Hoechst) and in Holland (Philips-Duphar). It
    is known that fentin compounds are also produced in the United States
    and Japan, but no data were available from these sources.

    Formulations

    The usual formulations are:

         fentin hydroxide    : 20 percent and 50 percent wp
         fentin acetate      : 20 percent and 60 percent wp
         fentin chloride     : 40 percent and 45 percent wp

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, distribution and excretion

    Experiments on rats given 113Sn-labelled fentin chloride showed that
    the absorbed fentin radical was rapidly distributed through the
    tissues of the body, including the brain. The fentin radical was
    eliminated relatively slowly and could be detected in the brain 38
    days after a single dose (Heath, 1963).

    Experimental investigations have been made on guinea pigs fed on a
    diet containing 12 ppm fentin acetate. From the survival times and the
    total amount consumed, it is evident that, at this dosage level,
    fentin compounds are not completely cumulative. The results obtained
    and those previously published (Stoner, 1966) are consistent with a
    halflife of the fentin radical at the site of action of about 50 days
    (Stoner and Heath, 1967).

    Information on the distribution of tin after feeding fentin compounds
    to farm animals is included in the section entitled "FATE OF
    RESIDUES. In animals".

    Effect on enzymes and other biochemical parameters

    In vitro studies have shown that fentin compounds inhibit oxidative
    phosphorylation by isolated liver mitochondria and the adenosine
    triphosphatase (ATP) activity of brain microcomes (50 percent
    inhibition by concentration of, 1 × 10-6M and 1 × 10-5M,
    respectively) (W. N. Aldridge, quoted by Stoner, 1966).

    The oxygen consumption of cerebral slices from rats in a moribund
    condition due to fentin compounds was within normal limits (J.E.
    Cremer, quoted by Stoner, 1966).

    The effects of fentin hydroxide on the oxidative phosphorylation and
    on permeability of rat liver mitochondria membranes for malate,
    citrate and fumarate ions were investigated. In the conditions of the
    investigations (concentration of 5 µ M), a strong inhibitory action on
    the oxidative phosphorylation in isolated rat liver mitochondria and
    deep changes in the selectively permeable mitochondrial membrane were
    observed. Malate and citrate were able to penetrate mitochondria
    without participation of any carrier. The altered membrane formed no
    barrier for fumarate. No similar effects were observed in the case of
    n-octyltin derivatives (Syrowatka, 1969).

    In a further investigation, it was shown that the mitochondrial
    membrane which, when intact, has a strictly limited permeability for
    K+, Na+, Cl-, malate, citrate and fumarate, became permeable in a
    high degree to these ions under the influence of fentin hydroxide.
    Electron microscopic pictures confirmed these results (Syrowatka,
    1970).

    TOXICOLOGICAL STUDIES

    Special studies on influence on lymphatic tissue and immune
    responses

    Guinea pig (fentin acetate)

    These investigations were aimed at studying the influence of fentin
    acetate on lymphatic tissue and immune responses in guinea pigs which
    were previously (see below) shown to be much more sensitive than rats
    to the decreasing effect of the compound on the lymphopoiesis. Female

    guinea pigs were selected because they are more affected than males.
    In a first experiment, two groups of ten female guinea pigs received
    15 ppm of fentin acetate in their diet, for 49 or 77 days. Each group
    was accompanied by a control group with the same number of animals.
    After 77 days, a decrease in plasma cells was observed in the spleen
    and the cervical, mesenteric, axillary and popliteal lymph nodes. In a
    second experiment, the same dose of the compound was given in the diet
    for 104 days. Two groups of ten female guinea pigs received fentin
    acetate and two groups control diet only. At 21 and 7 days before the
    end of the fentin acetate feeding period, half of the animals received
    an injection of tetanus toxoid. Some animals were allowed to recover
    for 14 days after the 104-day experimental period. Immunochemically
    and serologically, a decreased immunologic response was observed in
    the group fed fentin acetate after tetanus toxoid stimulation and no
    signs of recovery were seen after 14 days. With the aid of the
    fluorescent antibody technique, a decrease in immunologically active
    cells in the popliteal lymph nodes of the animals fed fentin acetate
    could be detected in the second experiment. In the other lymphatic
    tissues, no differences were observed (Verschuuren at al., 1970).

    Special studies on reproduction

    Rat (fentin acetate)

    An interim report comprising two generations of a three-generation
    reproduction study in rats fed 0, 25, 80 and 250 ppm of fentin acetate
    in the diet is available. No histological examination was performed,
    but no abnormalities were found by macroscopic examination at the 25
    ppm level (Scholz and Baeder, 1970).

    Rat (fentin acetate and chloride)

    Groups each of 20 sexually mature male rats (aged 35 to 40 days) were
    given orally in their food, over a period of 19 days, 20 mg/kg
    body-weight per day of either fentin acetate or fentin chloride. The
    animals were killed on the twentieth day, and histological
    preparations of the testes were made. Both compounds produced several
    degenerative changes of the testicular tissue, including a decrease in
    the number of cell layers per seminiferous tubule, a decrease in
    tubule diameter and overall testicular size, a depletion of the more
    advanced cell forms from the tubules and a closing of tubule lumina.
    Effects were more pronounced in animals treated with fentin acetate
    (Pate and Hays, 1968).

    Groups of 15 sexually mature female rats (aged 42 to 46 days) were
    given orally 20 mg/kg body-weight per day of either fentin acetate or
    fentin chloride. Three animals from each group were killed after 4, 9,
    14, 19 and 24 days of treatment, and histological preparations of the
    ovaries were made and thoroughly examined. Both fentin compounds
    produced significant changes in the ovarian tissue. Among these
    changes were a decreased number of mature follicles, an increased
    incidence of atresia in early follicle growth and a pronounced
    decrease in the number of corpora lutea present. This last effect was

    regarded as a decrease in ovulation and, thus, a decreased fertility.
    This effect, as well as the others listed above, was present on or by
    the first five-day sample period (Newton and Hays, 1968).

    Rat (fentin hydroxide)

    This experiment was started with 50 male and 100 female newly weaned
    rats. The animals were divided at random over five groups and were fed
    diets containing 0, 0.5, 1, 2 or 5 ppm of fentin hydroxide. Fertility
    of males and females, number of young born per litter, vitality,
    body-weight and mortality of the young at birth and during the
    lactation period were not affected by feeding fentin hydroxide at
    levels up to 5 ppm in any of the three successive generations.
    Ninety-day feeding studies with F1b and F2b generation rats did not
    reveal adverse effects with respect to growth, food consumption, food
    efficiency and haematology. Increased relative weights of liver,
    kidney and spleen were occasionally noted, but were not associated
    with histological abnormalities. Testicle weight was slightly
    decreased at the 5 ppm level in F1b generation rats and at the 2 and
    5 ppm levels in F2b generation rats at week 13 after weaning.
    Macroscopically, no changes attributable to the ingestion of fentin
    hydroxide were observed in any of the successive generations, except
    for small-sized testicles at feeding levels of 1 ppm and above in
    generation F3b at week 2 after weaning. Microscopic examination
    revealed a significant difference between treated and control rats
    only in the maturing testicle. This difference found expression in the
    stage of maturation of the germinal epithelium, which was less
    advanced in the small-sized testicles of the rats fed fentin hydroxide
    (Til et al., 1967).

    Four groups of ten weanling male rats were each fed 0, 50, 100 or 200
    ppm of fentin hydroxide in the diet over a period of 276 days and were
    mated at intervals to nontreated females. Observations indicate that,
    in comparison to the controls, there was a drop of about 27 and 18
    percent, respectively, in the total number of offspring in the groups
    fed 200 and 100 ppm after 64 days of exposure. However, when the males
    were subsequently mated, their fertility improved and, by day 113, was
    comparable to that of the controls. Leucocyte and differential counts
    and haemoglobin determinations performed one week prior to the time of
    sacrifice did not differ from the controls. Gross abnormalities
    related to fentin hydroxide were not observed in the offspring. In the
    group fed 200 ppm, one rat died and two were sacrificed when moribund.
    The cause of death in this group was generalized internal haemorrhage.
    In the animals that were sacrificed, no gross or microscopic
    abnormalities attributable to fentin hydroxide were observed. At the
    100 and 200 ppm levels, the food consumption of the diet containing
    fentin hydroxide was significantly lower during the first week of the
    experiment and then improved for all dosage levels. By week 7, the
    animals had adapted to these concentrations of the chemical, and the
    food consumption was the same as in the controls. The food intake and
    weight gain were not affected in rats fed 50 ppm. Gross and

    microscopic examination of rats fed fentin hydroxide at all levels did
    not reveal changes in any organ that could be related to the compound
    (Gaines and Kimbrough, 1968).

    Three experiments on weanling male rats (10 or 20 per group), fed from
    0 to 25 ppm of fentin hydroxide in two or four weeks, were conducted
    to determine testicular development. Microscopic examination after two
    and four weeks failed to reveal any differences between the various
    test groups and the control groups (Til et al., 1968).

    Acute toxicity

    Symptoms of poisoning were sluggishness, unsteadiness, moderate
    diarrhoea, anorexia, bloody stain around the nose and eyes and
    wheezing (Gaines and Kimbrough, 1968).

    In all species, the main action of these organo-tin compounds is
    thought to be on the central nervous system, but in contrast to
    triethyltin compounds, cerebral oedema did not occur (Cahen et al.,
    1970).

    Intravenous administration of fentin acetate to cats at a dose of 1
    mg/kg body-weight produced an increase in blood pressure and a short
    interruption of respiration followed by stimulation of respiration and
    clonic contractions of the limb muscles. Repeated administration of 1
    to 2 mg/kg at 20 to 60 minute intervals led to arterial hypotension. A
    decrease in the effect of noradrenaline on blood pressure was also
    found. Death took place after 6 to 14 mg/kg of fentin acetate from
    paralysis of the respiratory centres (Tauberger, 1963).

    Short-term studies

    Dog (fentin acetate)

    Groups of dogs (four of each sex) were fed 0, 1, 5 and 20 ppm of
    fentin acetate in the diet for 120 days. A level of 20 ppm resulted in
    decreased food consumption, and in half of the animals, also in
    decreased body-weight. No macroscopic or microscopic abnormalities
    were found (Scholz and Brunk, 1968a).

    Groups of six dogs, three from each sex, were fed over a period of two
    years, 0, 0.5, 1 or 5 ppm of fentin acetate. Attention was paid to
    behaviour, food intake, weight gain, blood picture, urine composition,
    gross examination and histological characteristics of the main organs
    and tissues. Except for the higher level, where a decrease in weight
    gain, which might be related to a reduction of food intake, was noted
    in comparison to the controls, no significant abnormalities, even in
    blood picture, were observed (Scholz and Brunk, 1968b).

    Dog (fentin hydroxide)

    Groups of dogs consisting of three males and three females were fed 0,
    10, 25 and 37 ppm of fentin hydroxide in the diet for 90 days.

        TABLE I
                                                                                        

    Acute toxicities to various species: summary

    Animal              Fentin                   LD50 (mg/kg
                        Compound        Route    body-weight)     Reference
                                                                                        

    Mouse      (M)      acetate         oral          81        Ueda et al., 1961

    Mouse      (M)      chloride        oral          80        Ueda et al., 1961

    Mouse      (M)      hydroxide       oral         245        Philips-Duphar, 1964a

    Mouse      (F)      hydroxide       oral         209        Philips-Duphar, 1964a

    Mouse      (M)      acetate         ip             7.9      Stoner, 1966

    Rat        (M)      acetate         oral         136        Klimmer, 1964

    Rat        (F)      acetate         oral         491        Stoner, 1966

    Rat        (F)      chloride        oral         135        Scholz, 1963

    Rat        (M)      hydroxide       oral         240        Gaines & Kimbrough, 1968

    Rat        (F)      hydroxide       oral         360        Gaines & Kimbrough, 1968

    Rat        (M)      acetate         ip             8.5      Stoner, 1966

    Rat        (F)      acetate         ip            11.9      Stoner, 1966

    Guinea pig (M)      acetate         oral          21        Klimmer, 1964

    Guinea pig (M)      hydroxide       oral          27.1      Philips-Duphar, 1964a

    Guinea pig (F)      hydroxide       oral          31.1      Philips-Duphar, 1964a

    Guinea pig (M)      acetate         ip             3.7      Stoner, 1966

    Rabbit     (M)      acetate         oral          40        Klimmer, 1964

    Rabbit     (M)      acetate         ip            10        Klimmer, 1964
                                                                                        
    
    Lethargy and a darkening of the hair occurred in all groups, depending
    in degree on the dosage, and an increased mortality rate occurred in
    the two higher groups (Baran et al., 1966a).

    Groups of dogs (three of each sex) were fed 0, 10, 25 and 37 ppm of
    fentin hydroxide in the diet for 100 days. Apart from darkening of the
    hair which occurred in all test groups, the only differences from the
    controls were lethargy in the 37 ppm dogs and an increased quantity of
    tin in the livers of five of six dogs at 37 ppm and two of six dogs at
    25 ppm (Baran et al., 1966b).

    Six dogs were fed, over a period of 16 weeks, a diet containing,
    during the first eight weeks, 25 ppm and, afterwards, 50 ppm of fentin
    hydroxide. Symptoms of toxicity, consisting principally in inhibition
    of growth, alterations in the blood picture (decrease of the number of
    leucocytes and erythrocytes) and in the histology of the liver, were
    observed (Til and Feron, 1965).

    Following this preliminary investigation, 34 dogs were fed over a
    period of two years a diet containing respectively 0, 0.5, 2.5, 5 and
    10 ppm. Growth, food consumption, symptomatology, blood picture, urine
    analysis, liver and kidney functional exploration, serum protein
    electrophoresis, water content of brain, organ weights and gross and
    microscopic pathology were used as criteria to disclose signs of
    injury. General appearance, behaviour, growth, food consumption,
    haematological and biochemical values, urine analyses and liver and
    kidney functional tests were not affected at any dietary level of the
    compound. At the two highest feeding levels of 5 and 10 ppm, the
    relative weights of liver and kidney and the water content of the
    brain were increased in comparison to the controls, without being
    associated with histological changes. Gross and microscopic
    examination of organs and tissues did not reveal any abnormality which
    could be attributed to the ingestion of fentin hydroxide (Til and
    Feron, 1968).

    Guinea pig (fentin acetate)

    In one experiment, 50 ppm of fentin acetate in the diet of guinea pigs
    led to the death of all of nine animals in 17 to 31 days. In other
    experiments, only a group of five guinea pigs given 1 ppm for 392 days
    did not show an increased mortality rate. Even at 1 ppm, food intake
    was reduced. When death occurred, it was preceded by loss of weight
    and generalized weakness (Stoner, 1966). Neither in these experiments,
    nor in others (acute and short-term), in which guinea pigs and rats
    have been treated with fentin compounds, has a significant increase in
    the water content of the central nervous system been found nor the
    characteristic histological lesion in the white matter produced by
    triethylin compounds (Magee et al., 1957) been seen (Stoner, 1966).

    In other experiments, groups of guinea pigs, 10 of each sex, were
    given respectively 0, 5, 10, 20 or 50 ppm of fentin acetate for 12
    weeks. In all groups, except for the males given 5 ppm, growth
    inhibition was obvious.

    At the end of the treatment, no animal at 50 ppm was alive; in the
    other groups, the survival rates were: 20 ppm, 8 out of 10 males and 8
    out of 10 females; 10 ppm, 9 out of 10 males and 10 out of 10 females;
    5 ppm, 9 out of 10 males and 10 out of 10 females. In the females on
    5, 10 and 20 ppm and males on 10 and 20 ppm, the number of lymphocytes
    and leucocytes was significantly decreased. The leuco- and lymphopenia
    was accompanied in a number of animals by histological changes in the
    lymphopoietic system, e.g., atrophy of the white pulp of the spleen
    was found. This change possibly induced a decrease of general
    resistance, so that a mycotic infection developed in the animals. At
    20 and 50 ppm, a significant increase of brain water was noticed.
    Histological findings were not significantly different from those
    observed in the controls (Verschuuren et al., 1966).

    Groups of guinea pigs, ten of each sex, were fed 0, 1, 5, 10, 50 and
    100 ppm of fentin acetate for four months. All animals on 100 ppm and
    30 percent of those on 50 ppm died, and in the same groups were found
    signs of disturbance of the iron metabolism. A level of 10 ppm gave a
    slight reduction in weight gain, as well as some cases of decreased
    haemoglobin percentage and total number of erythrocyte. The groups fed
    5 ppm and 1 ppm were similar to the controls (Scholz and Weigand,
    1968).

    Guinea pig (fentin hydroxide)

    Groups of three males and three females were given 0, 1, 2.5, 5 or 20
    ppm of fentin hydroxide for three weeks. No changes in the growth
    rate, the water content, or the histology of the nervous system were
    observed (Verschuuren at al., 1965).

    Groups of ten males and ten females were fed 0, 2.5, 5, 10, 20 or 50
    ppm of fentin hydroxide in their diet for 12 weeks. Growth depression
    was observed at the two highest dose levels. All animals in the 50 ppm
    group died during the first half, and one each in the ten and 20 ppm
    groups died later in the experiment. A decrease in the haemoglobin
    content was found in all groups, except for the males in the 2.5 and 5
    ppm groups there was no change in the number of erythocytes. A
    decrease in the number of leucocytes (except in the males on 10 ppm)
    and lymphocytes (except the males on 2.5 and 5 ppm) was found in all
    the groups examined. The same changes as with fentin acetate were
    found in the lymphopoietic system (see above). A decrease in relative
    organ weight was found in the spleen of the females on 10 and 20 ppm
    and in the thymus of both sexes and uterus and testes at 20 ppm. No
    increase in the water content of the central nervous system was
    observed, except in the females at 50 ppm. Apart from the changes in
    the lymphopoietic system, the histological findings were not
    significantly different from those observed in the controls
    (Verschuuren et al., 1966).

    See also Special studies on influence on lymphatic tissue and immune
    responses.

    Rat (fentin acetate)

    Groups of 20 to 25 rats were given fentin acetate by stomach tube at
    doses equivalent to 5, 10, 25 or 50 ppm for 105 to 170 days. At 50
    ppm, 70 percent of the rats died within 49 days. Nervous symptoms, as
    well as blood, urinary or histopathological changes, were not observed
    at the lower dose levels (Klimmer, 1964).

    In other experiments on rats, no deaths occurred during a ten-week
    period on 200 ppm of fentin acetate. These rats were then put on a
    diet containing 300 ppm, and five out of six rats died after a further
    117 to 168 days (Stoner, 1966).

    Groups of young rats, ten of each sex, were given respectively 0, 5,
    10, 25 or 50 ppm of fentin acetate for 12 weeks. Decrease of food
    intake and growth inhibition were recorded at 50 ppm, as well as
    growth inhibition in males at 25 ppm. At 10 ppm and above, the number
    of leucocytes in the blood was decreased in the male (leucopenia) and,
    at 50 ppm, the haemoglobin was reduced. At the highest level there was
    a decrease of the organ to heart weight ratio for the pituitary and
    pancreas in all animals and uterus and ovary in the females. The same
    ratio for the thyroid was decreased in all the females, as well as in
    the males at 25 and 50 ppm. Paralysis and pronation of the hind legs,
    associated with interstitial oedema of the central nervous system,
    which developed in rats treated with triethyltin hydroxide at all
    levels, were not observed. The water content of the spinal cord was
    slightly increased at 50 ppm. Histological findings were not
    significantly different from those observed in controls (Verschuuren
    at al., 1966).

    Groups of 20 young rats, ten of both sexes, were fed respectively, 0,
    15, 40, 100, 250 or 600 ppm of fentin acetate over a period of four
    months. Attention was given to behaviour, growth, blood picture, urine
    composition, gross examination and histology of the main organs and
    tissues. Up to 100 ppm, no abnormalities were observed in comparison
    to the controls. Above 100 ppm, a dose-related inhibition of growth
    was seen and 600 ppm resulted in the death of 30 percent of the
    treated animals. (Scholz and Baeder, 1968).

    Rat (fentin chloride)

    Groups of ten rats of both sexes were given orally, over a period of
    41 days, 28 doses of 0, 6.25, 12.5, 25 or 50 mg/kg body-weight. Apart
    from a slight decrease in weight gain of the females at 12.5 mg/kg, no
    abnormalities (growth, behaviour, blood picture and urine composition,
    gross and histological characteristics of stomach, small intestine,
    spleen, liver, kidney and lung) were observed at 6.25 and 12.5 mg/kg.
    At higher doses, a dose-related increase in mortality compared to the
    controls was observed (Scholz, 1963).

    Rat (fentin hydroxide)

    Groups of 10 or 20 rats of both sexes were given 0, 5, 20, 50 or 100
    ppm of fentin hydroxide for 20 days. Food intake and body growth were
    depressed at 20 ppm and above. Death rates were 9 out of 10 at 100
    ppm; 9 out of 20 at 50 ppm, and 1 out of 20 at both 20 and 5 ppm (Van
    Esch and Arnoldussen, 1962).

    Groups of rats, ten of each sex, were fed 0, 1, 3.1, 5, 10 and 31 ppm
    of fentin hydroxide in the diet for 90 days. Disregarding effects on
    erythrocyte and leucocyte counts as neither dose related nor
    chronologic, a no-effect level of 31 ppm was claimed (Wolf et al.,
    1966).

    Groups of ten rats of each sex were given respectively 0, 5, 10 or 25
    ppm of fentin hydroxide in the diet for 12 weeks. The food intake was
    comparable to the controls. The females showed growth inhibition after
    six weeks, but they recovered in spite of continuing treatment. Growth
    in the males was comparable to the controls. In the females, blood
    leucocytes were decreased. No significant changes in water content
    were found in the nervous tissues. At 25 ppm, decrease of the thyroid
    weight was noticed (Verschuuren at al., 1962). In a similar
    experiment, in which ten rats of each sex were given 50 ppm of the
    same compound, the following features were noticed: decreased food
    intake, growth inhibition in both sexes, decrease in weight of the
    thyroid, pituitary, uterus, ovary, prostate and pancreas, as well as
    decrease of haemoglobin and leucocytes. Paralysis and pronation of the
    hindlegs, associated with interstitial oedema of the central nervous
    system, which developed in rats treated with triethyltin hydroxide at
    all levels, were not observed. The water content increased in the
    spinal cord, but not in the brain. (In comparison, the water content
    of the spinal cord and brain was increased in animals treated with
    levels of 5 and 10 ppm of triethyltinhydroxide). Histological findings
    in the animals treated with fentin hydroxide were not significantly
    different from those observed in the controls (Verschuuren et al.,
    1966).

    Groups of four to five week old male rats were fed fentin hydroxide in
    the diet at levels of 0, 100, 200 or 400 ppm over a period of 99 days.
    The rats fed 400 ppm were apparently repelled, since they ate only
    about one third as much food as the controls during the first week.
    All the animals in this group died within 7 to 34 days from starvation
    and extensive intra-alveolar haemorrhage in the lung. There was
    partial or complete testicular atrophy and general size and weight
    reduction of the organs. The rats fed 200 ppm gained less weight (231
    g) than the controls (302 g). At the end of the study, the total
    leucocyte number and the weights of spleen and kidneys were
    significantly below those of the controls.

    The rats fed 100 ppm appeared normal throughout the study except for a
    significant decrease of food intake during the first week of treatment
    (Gaines and Kimbrough, 1968).

    Additional information on the findings following short-term
    administration of fentin compounds to rats is given under Special
    studies on reproduction.

    Long-term studies

    Guinea pig (fentin acetate)

    Groups of 20 young guinea pigs, ten from each sex, were fed
    respectively 0, 1, 5, 10, 50, 100 and 200 ppm of fentin acetate over a
    period of two years. Attention was given to behaviour, food intake,
    weight gain, blood picture, urine composition, gross examination and
    histological characteristics of the main organs and tissues. At 50 ppm
    and above, a dose-related increase in mortality in comparison to the
    controls and an inhibition of growth were observed. At 10 ppm and
    above, fatty degenerative changes were seen in liver and heart muscle.
    At 1 and 5 ppm, no abnormalities, even in the blood picture, were
    noted in comparison to the controls (Weigand and Kief, 1965).

    Rat (fentin hydroxide)

    Groups of 50 newly weaned rats, 25 from each sex, were fed over a
    period of two years respectively 0, 0.5, 1, 2, 5 or 10 ppm of fentin
    hydroxide. General appearance and behaviour, growth, food intake,
    blood sugar and blood urea nigrogen, urine composition and SG-PT,
    SG-OT and SAP activity were not adversely affected at any dietary
    level of the test substance. Mortality of the females at 10 ppm was
    higher than in the controls, although at the termination of the
    experiment the difference was not significant. Haematological data
    often showed a slight decrease in white blood cells at the highest
    feeding level in the first year of the experiment only. This effect
    was less often soon at 5 ppm and only once at 2 ppm in the males. The
    relative thyroid weight was slightly decreased at 10 ppm in the
    females only. Average relative weights of the other organs were very
    uniform in all groups. Gross autopsy findings did not show evidence of
    significant pathological changes. Microscopic examinations of numerous
    organs and tissues, including testes, ovaries and bone marrow, did not
    reveal histological alterations significantly different from those
    observed in controls (Til et al., 1970).

    COMMENTS

    The basis for grouping the three fentin compounds for consideration
    together is that fentin acetate and fentin chloride are converted in
    plants and animals to the same compound, namely fentin hydroxide.

    Since the previous toxicological evaluation of the fentin compounds in
    1965, a considerable number of short-term and long-term feeding
    studies in several species have been reported. The production of
    cerebral oedema in rats and guinea pigs did not appear to be
    pronounced except at a 50 ppm dose level. However, the reduction of
    lymphopoiesis in both species appeared to be of some concern. With
    respect to this parameter, the guinea pig appeared to be the most

    sensitive species studied. A reduction in lymphocyte count was evident
    in females at a dietary level of 2.5 ppm of fentin hydroxide. It was
    reported that this effect was not entirely reversible after 14 days'
    withdrawal from a test diet of 15 ppm of fentin acetate. In a two-year
    feeding study in rats a no-effect level of 2 ppm relative to decrease
    in white blood cells was evident.

    In a multigeneration rat reproduction study, reduction in testicular
    size was evident at 5 ppm in the F1b generation, at 2 ppm and above
    in the F2b generation and at 1 ppm in the F3b generation. In a
    second species, the dog, histological examination revealed no effect
    on any organ at feeding levels of up to 10 ppm for two years.

    There are no reports of observations of men exposed to this compound.

    Bearing the abovementioned observations in mind, the Committee
    considered the data adequate to establish an acceptable daily intake
    for the fentin compounds.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat: 2 ppm in the diet, equivalent to 0.1 mg/kg body-weight

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0 to 0.0005 mg/kg body-weight, applicable to fentin hydroxide,
         fentin acetate and fentin chloride and to the sum of each if more
         than one is involved

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

    All the three fentin compounds are nonsystemic fungicides used in many
    European countries, the United States, and several South American,
    African and Asiatic countries. On rice they are used against algae.

    Pre-harvest treatments

    Fentin compounds are recommended to control the following pests:

    Potatoes:                Phytophthora infestans de Bary
                             of the foliage and especially
                             the tubers, and

                             Alternaria solani J. u.Gr.

    Sugar beet:              Cercospora beticola Sacc.

    Celery and celeriac:     Septoria apii Chester

    Carrots:                 Alternaria porri f. dauci Neerg.

    Pecans:                  Fusicladium effusum, Gnomonia spp.,
                             Mycosphaerella caryigena Demaree & Cole

    Rice:                    various algae

    Groundnuts:              Cercospora spp.

    Coffee:                  Colletotrichum coffeanum Noack

    Cocoa:                   Phytophthora palmivora Butl.

    The usual rates of application are between 0.15 and 0.40 kg a.i/ha in
    600 to 1 000 litres of water. On coffee, the rate is 0.2 to 0.6 kg
    a.i/ha in more than 1 000 litres of water. For algae control on rice,
    the dosage is up to 1 kg a.i/ha in about 1 000 litres of water.

    Recommended rates of application and intervals applied between last
    treatment and harvest are as follows:

    Potatoes:           0.18 to 0.4 kg a.i./ha. 1-10 times
                        (generally between 2 and 5 times).
                        Safety period (in Germany) 7 days.

    Sugar beets:        0.18 to 0.4 kg a.i./ha. 1-3 treatments.

    Celery celeriac,    0.2 to 0.32 kg a.i./ha in 600-1 000 1
    carrot:             water, 1-7 treatments. (In Germany
                        safety period for celery of 3 weeks)

    Pecans:             0.22 to 0.54 kg a.i./ha, 2 to 8
                        treatments.

    Rice:               0.75 to 1 kg a.i./ha for algae control.

    Peanuts, coffee,    0.2 to 0.6 kg a.i./ha.
    cocoa:

    Post-harvest treatments

    No post-harvest treatments are recommended.

    Other uses

    Fentin compounds are used on ornamentals, willow and poplar. Trials on
    hops are in process.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    Residue data from supervised trials are given in Table II.


        TABLE II

    Summary of fentin compound residues in supervised trials
                                                                                                                                          

    Crop          Country       Rate of         Number        Preharvest     Plant       Detection     Number       Number of     Highest
                                application     of            interval       part        limit         of           residues      residues
                                (kg a.i/ha)     treatments    (days)         analyzed    (ppm)         analyses     under         found
                                                                                                                    detection     (ppm)
                                                                                                                    limit

                                        Residues of fentin hydroxide
                                                                                                                                          

    Potatoes      Holland       0.20-0.46         4-7         2-98           tubers      0.01           23           17            0.04
       "             "          0.08-0.38         6-7         98-110            "        0.06           14           12            0.11
       "          England       0.22-0.56           5         21-43             "        0.01            5            5
       "             "          0.28                1         30-35             "        0.03            6            6
       "          Canada        0.15-0.25        ?-12         ?-169             "        0.03            7            7
       "          U.S.A.        0.17-0.34        5-11         13-15             "        0.03           17           17
       "          Belgium       0.30-0.36           5         22                "        0.01            1            1
    Sugar beets   Holland       0.30                5         43-57          beets       0.03            4                         0.18
       "             "          0.30                5         43-57          leaves      0.06            4                         1.36
       "          Germany       0.30              1-4         46-64          beets       0.03            5            2            0.18
       "             "          0.30              1-4         46-64          leaves      0.06            5            2            0.81
       "          Italy         0.30-0.40           ?         31             beets       0.03           10            1            0.20
       "          Switzerl.     0.30-0.40           2         44             leaves      0.02            4                         2.45
       "          U.S.A.        0.22-0.34         3-6         14-45          beets       0.03           17            8            0.09
    Carrots       Israel        0.25-0.30         5-7         12-28          carrot      0.05            4            3            0.07
    Pecans        U.S.A.        0.22-0.54         2-8         46-256         nuts        0.03           17           17
    Rice          Italy         04-1.2 ppm          1         90             hulled rice 0.08            5            5
                                in irrigation
                                water

    TABLE II (cont'd)

    Summary of fentin compound residues in supervised trials
                                                                                                                                          

    Crop          Country       Rate of         Number        Preharvest     Plant       Detection     Number       Number of     Highest
                                application     of            interval       part        limit         of           residues      residues
                                (kg a.i/ha)     treatments    (days)         analyzed    (ppm)         analyses     under         found
                                                                                                                    detection     (ppm)
                                                                                                                    limit
                                        Residues of fentin hydroxide
                                                                                                                                          

    Ground nuts   U.S.A.        0.22-0.34         3-7         9-72           nuts        0.01           14           10            0.03
       "          U.S.A.        0.22-0.34         3-7         9-72           hulls       0.01           12            1            0.38
       "          U.S.A.        0.34              3-7         9              vines       0.01            3                         2.5
       "          Israel        0.30                4         5-23           nuts        0.01            4            4
       "            "           0.30                4         5-23           vines       0.16            4                         2.6
    Coffee        Kenya         0.22-0.60           ?         35             roasted     0.03            3            3
                                                                             beans

                                        Residues of fentin acetate
                                                                                                                                          
    Potatoes      Germany       0.216-0.324       1-5         7-21           tubers      0.03-0.04      12            8            0.07
       "          Ireland       0.3                 3         not stated        "        0.03            2            2
    Sugar beets   Germany       0.216-0.324         6         38             beets       0.1             6            6
    Celeriac         "          0.3               1-2         21-45          tubers      not stated      3            3
       "             "          0.324               1         21-35             "        0.1             3            3
       "          Belgium       not stated          3         21-28          stems       not stated      6            6
       "          Germany       0.3               1-2         21-45          leaves      not stated     13            2            0.19
       "             "          0.324               1         21-35             "        0.1             3                         3
       "          Holland       0.24-0.30         1-6         21-28             "        0.1             2                         1.0

    Celeriac      Holland       0.27                6         21-28          leaves      0.01            2                         0.30
       "          Belgium       not stated          3         21-28             "        not stated      6            5            0.05
    Carrots       Germany       0.216-0.324       1-3         7-28           1/          0.03           20           17            0.15
       "             "          0.216-0.324       1-3         7-28           2/          0.02            6            5            0.06
       "             "          0.216-0.324       1-3         7-28           3/          0.02            6            5            0.02
       "             "          0.216-0.324       1-3         7-28           4/          0.02            6            5            0.02

    TABLE II (cont'd)

    Summary of fentin compound residues in supervised trials
                                                                                                                                          

    Crop          Country       Rate of         Number        Preharvest     Plant       Detection     Number       Number of     Highest
                                application     of            interval       part        limit         of           residues      residues
                                (kg a.i/ha)     treatments    (days)         analyzed    (ppm)         analyses     under         found
                                                                                                                    detection     (ppm)
                                                                                                                    limit
                                        Residues of fentin acetate
                                                                                                                                          
    Rice          Italy         04-1.2ppm           1         appr.go        hulled      0.08            3            3
                                in irrigation                                 rice
                                 water
    Cocoa         Nigeria       not stated      not stated    not stated     not stated  0.1             8            7            0.1

                                        Residues of fentin chloride
                                                                                                                                          

    Potatoes      Germany       0.22-0.27         1-3         7-14           tubers      0.04            8            6            0.05
    Sugar beets      "          0.18-0.27           6         38             beets       0.10            4            4
    Celeriac         "          0.27                1         21-35          tubers      0.1             3            2            0.1
    Carrots          "          0.20                3         10-31          washed      0.02            4            2            0.08
                                                                              carrots
                                                                                                                                          
    1/ washed unpeeled carrots
    2/ peeled/scraped carrots
    3/ peels, calculated on total weight carrot
    4/ scrapings, calculated on total weight carrot
    

    The residue date of fentin hydroxide are from treatments made in the
    Netherlands, Germany, Belgium, Canada, England, Italy, Israel,
    Switzerland, U.S.A. and Kenya (Philips Duphar, 1963a, 1964b, 1965,
    1966a-d, 1968a,b; Thompson-Hayward, 1965a,b, 1967, 1969).

    The residue data of fentin acetate are from experiments made in
    Germany, the Netherlands, Belgium, Ireland, Italy, Kenya and Nigeria
    (Hoechst, 1963, 1964, 1965a, 1966a-d, 1967, 1968a-f,m,o,q, 1969c,d;
    Hardon et al., 1962; Gembloux, 1968; Food Inspection, 1965a-b;
    Kröller, 1960; Nat. Inst. Publ. Health, 1960; Philips Duphar, 1967).

    The residue date of fentin chloride are from experiments made in
    Germany (Hoechst, 1966e-h, 1968g-l,n,p, 1969a,b).

    FATE OF RESIDUES

    General comments

    When triphenyltin acetate was decomposed in solution, the following
    products were detected: phenol, acetone, hydrogen peroxide, degraded
    organotin and benzene. There is probably also some organic or
    organotin peroxide present (Hedges, 1961).

    In the presence of light and humidity, fentin acetate and fentin
    chloride are transformed easily into fentin hydroxide, which
    metabolizes into dephenyltin and monophenyltin. Monophenyltin breaks
    down very quickly into Sn salts (Kröller, 1960; Hoechst, 1961; Hedges,
    1961).

    At heating, triphenyltin hydroxide readily decomposes (see other
    relevant chemical properties).

    In animals

    After ingestion of fentin compounds by cows or sheep, the compound is
    largely excreted with the faeces (Herok and Götte, 1961; Brügemann et
    al., 1964). Three sheep given 10 mg daily of 113Sn-labelled fentin
    acetate for 25 days were killed respectively 28, 52 and 218 days after
    the beginning of the treatment. 113Sn was found in the milk (average
    concentration: 0.0017 ppm) during the treatment, but 17 days after
    withdrawal of the compound, its concentration in the milk was near
    detectable limits. Tin was present in the milk in at least two forms
    other than fentin acetate. During the treatment, the concentration of
    113Sn in the blood and in the urine were 2.9µg/1 and 7.5µg/1,
    respectively. In the sheep killed at 28 days, liver, kidney, lung,
    pancreas, gall bladder and brain contained a greater amount of 113Sn
    than other organs. After 218 days, the amount of 113Sn found in the
    liver was still greater than in other organs (Herok and Götte, 1961).

    Organs of one sheep, sacrificed at the end of the feeding period with
    the 113Sn triphenyltin acetate, showed the following residues
    (comprising triphenyltin and all degradation products including
    inorganic tin):

                                                       
                   Organ               ppm 113Sn
                                                       
                   liver               0.9
                   intestinal fat      0.01
                   depot fat           0.01
                   muscles             0.02
                                                       

    In plants

    Studies on the effect of tin compounds on plants have been made or are
    in progress in several laboratories. It has been shown that in the
    presence of light and air, several byproducts of fentin acetate can be
    formed, such as diphenyltin and finally insoluble tin (Kröller, 1960).
    The tin content from the leaves can be transferred to the ground.
    However, when 113Sn-labelled fentin acetate or hydroxide was applied
    to potato foliage, no translocation of 113Sn from leaves to tubers
    could be demonstrated above the limit of determination of 0.0001 ppm.
    Tin could be detected in the haulm, where the percentage of the
    original compound decreased for 20 days (Philips Duphar, 1964b). It
    has also been shown that fentin compounds have no systemic action when
    applied to celeriac and sugar beet (Herok and Götte, 1963).
    Furthermore, there is no uptake of phenyltin from the soil
    (Philips-Duphar, 1970; Hoechst, 1965b). This means that residues on
    food or feed can only result from direct contact with the pesticide or
    from contamination during harvest, transport or processing: potatoes,
    carrots, sugar beets, groundnuts, coffee, cocoa, pecans and rice are
    examples.

    With a few crops, the plant parts carrying the residues may be used as
    food or feed. Those feedstuffs are sugar beet tops and leaves,
    groundnut vines and rice hulls. As reported in "Fate of residues in
    animals" fentin itself and its degradation products in feed are
    transferred only in very small amounts into milk and meat (Brüggemann
    et al; 1964; Herok and Götte, 1963, 1964). The only crop from which
    the leaves are used for human consumption is celery. This crop forms
    generally only a small portion of the human diet.

    In soil

    Fentin compounds are degraded in soil almost completely within one
    year (Hoechst, 1967).

    Evidence of residues in food in commerce or at consumption

    No experimental data are available on the fentin residues in food
    moving in commerce or in the diets. Theoretically, it can be

    postulated, however, that the chance fentin compounds would reach the
    consumer is very limited. This is mainly due to the fact that the
    residues of fentin compounds or their metabolites occur only on the
    surfaces of those plant parts which have been subjects of direct
    treatments, or of other types of contamination, and are therefore
    easily removed by peeling, washing, shelling, etc., and are readily
    broken down in thermal processes.

    Peeling of potatoes, as well as cooking or other types of processing,
    are apt to remove the residues. After sugar beets are processed into
    sugar, no organic tin is found in sugar (Thompson and Hayward, 1969).
    Carrots generally are washed, scraped, peeled or cooked before
    consumption, which processes reduce the residues. The removal of
    shells of pecans, groundnuts and cocoa removes also the residues. The
    coffee beans are protected from contamination by the fruit peel and
    flesh, by fermentation and by roasting. Rice is protected by husk,
    which is removed by milling before the rice is cooked or baked for
    consumption. Celery and celeriac if used uncooked for human
    consumption may contain fentin residues at the time of consumption.
    The portion of these crops is, however, generally very small in human
    diets.

    The foliage of treated crops may contain fentin residues which have to
    be regarded as contaminants of animal feed. During silage the residues
    are, however, found to be degraded and the risk of contamination of
    animal products is avoided.

    METHODS OF RESIDUE ANALYSIS

    Fentin residues can be determined with two completely equivalent
    methods which give the same results in identical samples. In the
    method of Philips-Duphar, the triphenyltin compounds are determined
    absorptiometrically in the extract with pyrocatechol-violet at 630 mm.
    The detection limit of the method is between 0.01 and 0.12 ppm (Ross
    and White, 1961; Malát, 1962). In the method of Hoechst, the
    triphenyltin compound is converted into the tetrabromo compound,
    separated from traces of lead and then determined polarographically.
    The detection limit of the method is between 0.012 and 0.26 ppm (Bock
    and Gorbach, 1958; Bock et al., 1958; Bürger, 1961a,b; Deutsche
    Forschungsgemeinschaft, 1969).

    Because blank values are varying according to crop variety and origin,
    the detection limit is not a constant figure. None of the methods can
    distinguish between the three fentin compounds; they give the sum of
    these compounds. Di- and monophenyltin are not detected by these
    methods. Although methods to distinguish between tri-, di- and
    monophenyltin are available, some difficulties are encountered in the
    presence of organic matter. Work on that subject is going on. For the
    evaluation of residues in the abovementioned crops - with exception of
    celery - the determination of degradation products of the three fentin
    compounds does not seem relevant (see 113Sn-trials).

    There are a number of industrial reports on the analytical methods
    (see References).

    APPRAISAL

    Fentin compounds evaluated by the Working Party were fentin acetate
    (triphenyltin acetate), fentin chloride (triphenyltin chloride) and
    fentin hydroxide (triphenyltin hydroxide). They are used on potato,
    sugar beet, celery, celeriac, leek, carrot, hops, groundnuts, pecans,
    coffee and cocoa in various parts of the world to control fungus
    diseases and on rice to control algae. They are usually applied to the
    crops as a suspension of wettable powder.

    Residue data are available from many countries: on fentin acetate from
    different European and American countries, on fentin hydroxide from
    U.S.A. and a number of European countries and on fentin chloride from
    Germany.

    The fentin compounds are subject to a gradual degradation. Fentin
    acetate and fentin chloride produce at first triphenyltin hydroxide
    which degrades to di- and monophenyltin hydroxide, and finally results
    in the release of tin as inorganic tin salts. Among the other
    degradation products, phenol, benzene and hydrogen peroxide are found.
    The inorganic tin released from the organic molecule is not considered
    as a residue of fentin compounds, but as a mineral element of
    foodstuffs, and should be treated as such for regulatory purposes. The
    degradation of fentin compounds is accelerated by sunlight, humidity,
    thermal processes, etc. Due to the location of the residues on the
    surface of the plants, washing has been found to cause a considerable
    reduction of the residue levels. In soil, phenyltin residues degrade
    almost completely within one year.

    As was demonstrated with a radiolabelled (113Sn) compound in various
    crops, neither phenyltin compounds nor their degradation products are
    translocated within the plant after application to the leaves; neither
    is there any uptake of phenyltin from soil. This means that residues
    on food and feed can only result from direct contact with the
    pesticide. None or negligible residues of the fentin compounds and
    their metabolites can be expected at the time of consumption in the
    edible parts of such crops as potatoes, carrots, groundnuts, coffee,
    maize, pecans and rice. In the roots of sugar beets the residues are
    normally very small and, in addition, any residues are eliminated
    during processing.

    The foliage of treated sugar beets has been found to contain residues.
    During the silage process fentin compounds are broken down into
    inorganic tin in about a month.

    The fate of fentin compounds in cows has been evaluated by feeding
    animals with sugar beet leaves containing about 1 ppm fentin acetate.
    Only about 10 percent of the amount fed was absorbed from the


        NATIONAL TOLERANCES
                                                                                                    

    Compound              Country              Crop                       Tolerance
                                                                                                    

    Fentin hydroxide      U.S.A.               potatoes                   0.05 ppm
                                               sugar beets                under consideration
                                               pecans                     extended
                                               groundnuts                 under consideration

    Fentin                The Netherlands      potatoes                   zero
                                               celery and celeriac        1.0 ppm

    Fentin hydroxide      Federal Republic     celery leaves              1.0 ppm calculated as tin
    and fentin acetate    of Germany

    Fentin                Yugoslavia           generally                  1.0 ppm calculated as tin

                          Belgium              fruit and vegetables       zero
                                               celery and celeriac        1.0 ppm
                                                                                                    
    

    intestinal tract. Milk contained ca. 0.004 ppm of fentin in unchanged
    and changed form. Similar results have been obtained in a study on
    sheep, administered 113Sn labelled fentin acetate, when it was shown
    that the tin was finally excreted in inorganic form. In view of these
    results, the risks that fentin would contaminate milk are negligible.

    Two equivalent methods are available for the analysis of triphenyltin
    residues. The sensitivity of a colorimetric method is, depending on
    the type of crop, about 0.01 to 0.1 ppm and that of a polarographic
    method about 0.01 to 0.3 ppm. The various triphenyltin compounds are
    not distinguished by these methods: the analytical results therefore
    reflect the total amount of these compounds in a particular sample
    analysed.

    Although methods to distinguish between tri-, di- and monophenyltin
    are available (e.g. by TLC), difficulties are encountered in the
    presence of organic material. Work on that subject is going on. For
    the evaluation of residues in the above mentioned crops, with the
    exception of celery leaves, the determination of degradation products
    of fentin compounds does not seem relevant.

    RECOMMENDATIONS

    General provisions

    Foliage of the treated crops, as well as other parts of plants which
    may contain fentin residues, are not recommended to be fed fresh to
    domestic animals, but they should be used only as silage. Due to the
    degradation of the fentin compounds during silo storage, there is no
    need, at this stage of knowledge, to establish practical residue
    limits of meat and milk.

    Recommendations for tolerances

    Since the residues of fentins in the following crops were found to be
    less than the detection limits of the analytical methods, no
    tolerances are recommended: rice (detection limit: 0.08 ppm), cocoa
    (0.1 ppm), pecans (0.03 ppm) and coffee (0.03 ppm).

    Tolerances recommended refer to the total amount of fentin compounds
    expressed in terms of triphenyltin hydroxide. (Di- and monophenyltin
    and inorganic tin are not included in the figures.) The
    recommendations are also made on the assumption that the crops are
    treated according to good agricultural practice with one compound or,
    if two or three are integrated, at a maximum total rate recommended
    for any one of the three fentin compounds.

    TOLERANCES RECOMMENDED
                                                              
                             Parts          Based on period
                             per million    from treatment
                                            to harvest
                                                              

    PotatoesX                0.1            7 days
    Sugar beetsX             0.2            14 days
    CeleryX                  1              21 days
    CeleriacX                0.1            21 days
    CarrotsX                 0.2            7 days
    Groundnuts (shell-free)  0.05           7 days
                                                              

    XEssentially soil-free

    FURTHER WORK OR INFORMATION

    REQUIRED (by 30 June 1972)

    1. Reliable analytical methods capable of distinguishing qualitatively
       between fentin compounds and tricyclohexyltin hydroxide or other
       organotin compounds and, where possible, of quantitative 
       measurement of the separate compounds.

    2. Data on the occurrence of monophenyltin and diphenyltin compounds
       in the residues in celery.

    DESIRABLE

    1. More information on the effect of fentin compounds on the
       reticuloendothelial system, especially with respect to the
       reversibility of this effect.

    2. Reports of toxicological observations in plant workers involved in
       the manufacture of these compounds.

    3. Further studies on the effect on spermatogenesis.

    REFERENCES

    Baran, J., Fancher, O.E. and Calandra, J.C. (1966a) 90 day subacute
    oral toxicity of technical triphenyltin hydroxide - beagle dogs.
    Unpublished report from Industrial Bio-test Laboratories Inc., no IBT
    C3964 submitted to Thompson-Hayward Chemical Co.

    Baran, J., Fancher, O.E. and Calandra, J.C. (1966b) 100 days subacute
    oral toxicity of technical triphenyltin hydroxide - beagle dogs.
    Unpublished report from Industrial Bio-test Laboratories Inc., no IBT
    C4343 submitted to Thompson-Hayward Chemical Co.

    Bock, R. and Gorbach, S. (1958) Die Bestimmung kleiner Mengen von
    Triphenylzinnacetat in Pflanzenmaterial. Z. analyt. Chem., 163:
    429-432

    Bock, R., Gorbach, S. and Oeser, H. (1958) Analyse von
    Triphenylzinnverbindungen. Angew. Chem., 70: 272

    Brügemann, J., Barth, K. and Nieser, K.H. (1964) Experimentelle
    Studien über das Auftreten von Triphenylzinnacetat Rückständen in
    Rübenblättern, Rübenblattsilage, damit gefütterten Tieren und deren
    Ausscheidungs-produkten. Zbl. Yet. Med., 11: 4-19

    Bürger, K. (1961a) Zur Analytik von Organozinnverbindungen. Z.
    Lebensmittel-Unters. u. -Forschung, 114: 1-10

    Bürger, K. (1961a) Bestimmung von Mikrogramm-Mengen Zinn in tierischem
    und Pflanzlichem Material nach der Dithiolmethode. Z.
    Lebensmittel-Unters. u.-Forschung, 114; 10-13

    Cahen, R., Boucard, M., Lalaurie, M. and Lacour, C. (1970) Production
    expérimentale d'oedème cérébrale. C.R. Acad. Sci., (Paris) (in press)

    Deutsche Forschungsgemeinschaft. (1969) Rückstandsanalytik von 
    Pflanzenschutzmitteln. Verlag Chemie GmbH, Weinheim/Bergstrasse.
    Methode 55-B-1

    FAO/WHO (1965) Evaluation of the toxicity of pesticide residues in
    food. FAO Meeting Report No. PL/1965/10/1; WHO/Food Add./27.65

    Food Inspection Laboratory, Amsterdam. (1962) Pesticide Report KvW 58,
    dated August 1962, unpublished

    Food Inspection Laboratory, Amsterdam. (1965a) Pesticide Report KvW
    112, dated February 1965, unpublished

    Food Inspection Laboratory, Amsterdam. (1965b) Pesticide Report KvW
    115, dated May 1965, unpublished

    Gaines, Th.B. and Kimbrough, R.D. (1968) Toxicity of fentin hydroxide.
    Toxicol. appl. Pharmacol., 12:397-403

    Gembloux Centre de Recherches de Phytopharmacie, Gembloux. (1968)
    Report No. 34/68, dated June 1968

    Hardon, H.J., Besemer, A.F.H. et al. (1962) Feldversuche mit 
    Triphenylzinn. Dtsch Lebensmitl. Rdsch, 58: 349-352

    Heath, D.F. (1963) Some problems in the determination of residues in
    plants and mammals in "Radiation and Radioisotopes applied to Insects
    of Agricultural Importance", IAEA, Vienna, p. 185-193

    Hedges (1961) Letter of the Tin Research Institute, dated 3-8-1961
    with attached report

    Herok, J. and Götte, H. (1961) The radiometrical estimation of the
    distribution and excretion of (113Sn) triphenyltin acetate in
    ruminants. Symp. radioisotopes in animal biology, Mexico City,
    p.177-188

    Herok, J. and Götte, H. (1963) Radiometrische Untersuchungen über das
    Verhalten von Triphenylzinnacetat in Pflanze und Tier. Internat.J.
    Appl. Radiation and Isotopes, 14: 461-479

    Herok, J. and Götte, H. (1964) Radiometrische Stoffwechselbilanz von
    Triphenylzinnazetat beim Milchschaf. Zbl. Vet. Med. A 11, 20-28

    Hoechst Unpublished report (1961) Ing. Rei/kn(A), dated 22-8-1961 
    with attachment

    Hoechst Unpublished report (1963) Dr.Cz/Bi 3543, dated 15-3-1963

    Hoechst Unpublished report (1964) Dr.Cz/bi, dated 2-11-1964

    Hoechst Unpublished report (1965a) Dr.Cz/bi, dated 17-9-1965

    Hoechst Unpublished report (1965b) Hk/da-4565 b, dated 11-11-1965

    Hoechst Unpublished report (1966a) 1/67 1 t/m 4

    Hoechst Unpublished report (1966b) 94/66 1 t/m 4

    Hoechst Unpublished report (1966c) 94/66 1 t/m 4 

    Hoechst Unpublished report (1966d) 62/661-2. 70/66 3, 82/66 4

    Hoechst Unpublished report (1966e) 94/66 2 t/m 4

    Hoechst Unpublished report (1966f) 95/66 1-2

    Hoechst Unpublished report (1966g) 83/66 2 t/m 4

    Hoechst Unpublished report (1966h) 61/66 3, 69/66 3, 83/66 41 94/66 5

    Hoechst Unpublished report (1967) 84,90/66, dated 3-5-1967

    Hoechst Unpublished report (1968a) A1/67 IV, dated 6-6-1968

    Hoechst Unpublished report (1968b) 150/67, dated 29-5-1968

    Hoechst Unpublished report (1968c) 151/67, dated 29-5-1968

    Hoechst Unpublished report (1968d) 152/67, dated 29-5-1968

    Hoechst Unpublished report (1968e) 160/67, dated 5-7-1968

    Hoechst Unpublished report (1968f) 161/67, dated 5-7-1968

    Hoechst Unpublished report (1968g) A1/67 V, dated 6-6-1968

    Hoechst Unpublished report (1968h) 153/67, dated 29-5-1968

    Hoechst Unpublished report (1968i) 154/67, dated 29-5-1968

    Hoechst Unpublished report (1968j) 155/67, dated 29-5-1968

    Hoechst Unpublished report (1968k) 1962/67, dated 5-7-1968

    Hoechst Unpublished report (1968l) 163/67, dated 5-7-1968

    Hoechst Unpublished report (1968m) 241/67, dated 5-3-1968

    Hoechst Unpublished report (1968n) 240/67, dated 5-3-1968

    Hoechst Unpublished report (1968o) 17/67, dated 1-4-1968

    Hoechst Unpublished report (1968p) 16/67, dated 1-4-1968

    Hoechst Unpublished report (1968q) 47/68, 99/68, 100 t/m 102/68

    Hoechst Unpublished report (1969a) I-14-68, 1 zu 7/8 + 14/68, dated
    7-8-1969

    Hoechst Unpublished report (1969b) I-13-68, I zu 13-68, dated
    20-6-1969

    Hoechst Unpublished report (1969c) IV-9-68, IV zu 7-11/68, dated
    7-11-1969

    Hoechst Unpublished report (1969d) IV-7-68, IV zu 7-11/68, dated 
    7-11-1969

    Klimmer, O.R. (1964) Toxikologische Untersuchungen mit
    Triphenylzinnacetat. Zbl. Vet. Med., 11:29-39

    Kröller, E. (1960) Triphenylzinnverbindungen im Pflanzenschutz und
    ihre Rückstandsbestimmung. Dtsch. Lebensmitt-Rdsch. 7: 190-193

    Kröller, E. (1960) Triphenylzinnverbindungen im Pflanzenschutz und
    ihre Rückstandsbestimmung. Dtsch. Lebensmittel-Rdsch., 56: 190-193

    Magee, P.N., Stoner, H.B. and Barnes, J.M. (1957) The experimental
    production of oedema in the central nervous system of the rat by
    triethyltin compounds. J. Path. Bact., 73: 107-124

    Malát, M. (1962) Photometrische Zinnbestimmung mit
    Brenzcatechinviolett in Anwesenheit von Gelatine; Colorimetrische
    Studien (III). Anal. Chem., 187: 404-409

    Nat. Inst. Public Health. (1960) Unpublished report nr. FT/17/60, 
    dated 23-4-1960

    Newton, D.W. and Hays, R.L. (1968) Histological studies of ovaries in
    rats treated with hydroxyurea, tri-phenyltin acetate and triphenyl
    chloride. J. econ. Entomol., 61: 1668-1669

    Pate, B.D. and Hays, R.L. (1968) Histological studies of testes in
    rats treated with certain insect chemosterilants. J. econ. Entomol.,
    61: 32-34

    Philips Duphar Unpublished report (1963a) 56655/2A/63

    Philips Duphar Unpublished report (1963b) 56655/38/63

    Philips Duphar Unpublished report (1964a) 56646/5/64

    Philips Duphar Unpublished report (1964b) 56655/34/63

    Philips Duphar Unpublished report (1965) 56655/64/65

    Philips Duphar Unpublished report (1966a) 56655/15/66

    Philips Duphar Unpublished report (1966b) 56655/47A/66

    Philips Duphar Unpublished report (1966c) 56655/54/66

    Philips Duphar Unpublished report (1966d) 56655/61/66

    Philips Duphar Unpublished report (1967) 56655/2/67

    Philips Duphar Unpublished report (1968a) 56655/14/68

    Philips Duphar Unpublished report (1968b) 56655/17/68

    Philips Duphar Unpublished report (1970) 566461/1/70

    Ross, W.J. and White, J.C. (1961) Application of pyrocatechol violet
    as a colorimetric reagent for tin. Anal. Chem., 33:421-427

    Scholz, D. (1963) Toxikologische Prüfung von Triphenylzinnchlorid und
    Hoechst 2840-Spritzpulver. Unpublished report from Hoechst A.G., 18
    December 1963

    Scholz, D. and Baeder, M. (1968) Berichte über ein chronische 
    Toxizitätsprüfung von Triphenylzinnacetat per os an Ratten (4 Monate).
    Unpublished report from Hoechst A.G.

    Schulz, D. and Baeder, O. (1970) Berichte über fortpflanzungsversuche
    mit triphenylzinnacetat an Ratten (Einflues auf Fertilitat,
    Gravidität, postnatale Entvicklung). Unpublished report from Hoechst
    AG

    Scholz, D. and Brunk. (1968a) Chronische oral toxizitätsprufung von
    Triphenylzinnacetat (Brestan-Wirkstoff) 120 Tage-Versuch an Hunden.
    Unpublished report from Hoechst A.G.

    Scholz, D. and Brunk. (1968b) Chronische oral toxizitätsprafung von
    Brestan-Wirkstoff 2-Jahres-Versuch an Hunden. Unpublished report from
    Hoechst A.G.

    Scholz, D. and Weigand. (1968) Triphenylzinnacetat.
    Wirkstoff-Technische. 4-Monate-Futterungsversuch an Meerschweinchen.
    Unpublished report from Hoechst A.G.

    Stoner, H.B. (1966) Toxicity of triphenyltin. Brit. J. industr. Med.,
    23: 222-229

    Stoner, H.B. and Heath, D.F. (1967) The cummulative action of
    triphenyltin. Fd. Cosmet. Toxicol., 5: 285-286

    Syrowatka, T. (1969) Investigation of the action of organotin
    compounds on the oxidative phosphorylation and permeability of
    membrane of rat liver mitochondria Roczn. Zak. Hig. (Warsz.), 20:
    717-725

    Syrowatka, T. (1970) Influence of fungicides on cellular energetic
    processes. Roczn. Zak. Hig. (Warsz.), 21: 105-115

    Tauberger, G. (1963) Tierexperimentelle Analyse der
    Triphenylzinnwirkung nach intravenöser Injektion. Med. exp. (Basel),
    9: 393-399

    Thompson-Hayward Unpublished report (1965a) R-542 

    Thompson-Hayward Unpublished report (1965b) R-568 

    Thompson-Hayward Unpublished report (1967) R-650 

    Thompson-Hayward Unpublished report (1969) R-755 

    Til, H.P. and Feron, V.J. (1965) Triphenyltinhydroxide range-finding
    test with dogs. Unpublished TNO report submitted by Philips-Suphar,
    No. R-1994

    Til, H.P., Feron, V.J. and de Groot, A.P. (1967) Reproduction study
    with triphenyltinhydroxide in three generations of rats. Unpublished
    TNO report submitted by Philips-Duphar, No. 2476

    Til, H.P. and Feron, V.J. (1968) Chronic (two-year) toxicity study
    with triphenyltinhydroxide (TPTH) in beagle dogs. Unpublished TNO
    report submitted by Philips-Duphar, No. 2717

    Til, H.P., Feron, V.J. and der Groot, A.P. (1968) Observations on a
    possible effect of TPTH on testicular development in rats. Unpublished
    TNO report No. R 2620 submitted by Philips-Duphar.

    Til, H.P., Feron, V.J. and de Groot, A.P. (1970) Chronic toxicity
    study with triphenyltinhydroxide in rats for two years. Unpublished
    TNO report submitted by Philips-Duphar, No. R-3138

    Ueda, K., Iijima, K. and Yoshida, S. (1961) Acute oral toxicity of
    organotin compounds for mice. Unpublished report from Tokyo Dental
    College submitted to Sankyo Chemical Co.

    Van Esch, G.J. and Arnoldussen, A.M. (1962) Range-finding test as to
    the toxicity of triphenyltinhydroxide during 18 days. Unpublished
    report of the National Institute of Public Health, Utrecht, No. Tox
    39/62

    Verschuuren, H.G., Kroes, R. and van Esch, G.J. (1965) Semi-chronic
    investigation as to the toxicity of triphenyltinhydroxide in guinea
    pigs. Unpublished report of the National Institute of Public Health,
    Utrecht, No. Tox. 33/65

    Verschuuren, H.G., Kroes, R. Vink, H.H. and van Esch, G.J. (1966)
    Short-term toxicity studies with triphenyltin compounds in rats and
    guinea-pigs. Fd. Cosmet. Toxicol., 4: 35-45

    Verschuuren, H.G., Ruitenberg, E.J., Peetoom, F., Helleman, P.W. and
    van Esch, G.J. (1970) Influence of triphenyltin acetate on lymphatic
    tissue and immune responses in guinea pigs. Toxicol. appl. Pharmacol.,
    16: 400-410

    Weigand and Kief, Brestan-Wirkstoff (1965) 96 percent ig = 
    Triphenylzinnacetate 96 percent ig Chronischer Futterungsversuch.
    Meerschweinchen. Unpublished report from Hoechst A.G., 25 May 1965

    Wolf, C., Fancher, O.E. and Calandra, J.C. (1966) 90 day sub-acute
    oral toxicity of triphenyltin hydroxide - albino rats. Unpublished
    report from Industrial Bio-test Laboratories Inc., submitted to
    Thompson-Hayward Chemical Co.

    PART II

    LIST OF INDUSTRIAL REPORTS ON ANALYTICAL METHODS

    Philips Duphar L3-52-16.      Clean-up for the residue determination
                                  of triphenyltin compounds in vegetable
                                  matter.

    Philips Duphar L3-52-18.      Clean-up for the residue determination
                                  of triphenyltin compounds in potatoes.

    Philips Duphar L3-52-19.      Absorptiometric determination of tin in
                                  cleaned-up residues.

    Philips Duphar L3-52-21.      Clean-up for the residue determination
                                  of fentin hydroxide in rice.

    Philips Duphar L3-52-23.      Clean-up for the residue determination
                                  of triphenyltin compounds in tomatoes,
                                  carrots, onions and butter-beans.

    Philips Duphar L3-52-25.      Clean-up for the residue determination
                                  of triphenyltin compounds in
                                  sugar-beets.

    Philips Duphar L3-52-26.      Clean-up for the residue determination
                                  of triphenyltin compounds in celery and
                                  sugar-beets.

    Philips Duphar L3-52-29.      Clean-up for the residue determination
                                  of triphenyltin compounds in roasted
                                  coffee-beans.

    Farbwerke Hoechst.       Die Bestimmung kleiner Mengen von
    1966                     Triphenylzinn in Pflanzenmaterial (Dr.
                             Gorbach 111/66 dated 1-12-1966).

    Thompson-Hayward.        Clean-up for the polarographic residue
    1965a                    determination of triphenyltin compounds in
                             potatoes + polarographic tin determination in
                             pre-cleaned residues (from report 2-542).

    Thompson-Hayward.        Clean-up for the polarographic residue
    1965b                    determination of triphenyltin compounds in
                             pecans + polarographic determination of
                             inorganic tin (from report R-568).

    Thompson-Hayward.        Clean-up procedure for the colorimetric
    1967                     residue determination of triphenyltin
                             compounds in peanuts (from report R-650).
    


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