CYHEXATIN           JMPR 1978


         The 1973 Joint Meeting (FAO/WHO, 1974b) set a practical
    residue limit, now called an extraneous residue limit (ERL), for
    milk of 0.05 mg/kg (fat basis). This level was at or about the
    limit of determination. The present Meeting considered new data
    which indicated that the limit should now apply to whole milk and
    milk products. The use of cyhexatin to control certain pests of
    animals by direct application requires that the maximum residue
    levels should be re-examined in the light of new residue data from
    supervised trials, and that limits for meat, milk and milk products
    should now be MRLs rather than ERLs.

         New information was also received on some of the toxicological
    requirements listed at the 1970 Meeting, and on uses and residue
    levels in countries other than the U.S.A.



    Special studies on carcinogenicity

         Sprague-Dawley rats (50 m + 50 f per group) were fed a diet
    with 0, 1, 3 and 6 mg cyhexatin1/kg b.w./day for 2 years.
    Parameters evaluated included general appearance, mortality, body
    weight, food consumption, absolute and relative organ weights,
    gross morphology and detailed microscopy. Body weight and food
    consumption were decreased and general debilitation noted in males
    and females at the 3 and 6 mg/kg/day dosage, and body weights were
    decreased in females in the 1 mg/kg/day group after about 450 days
    on the diet. The 3 and 6 mg dose groups also showed atrophy of the
    skeletal muscles of hip and thigh, particularly in females of the
    highest dose group accompanied by a mild to moderate degenerative
    myophathy. These changes in many rats were associated with variable
    degrees of microscopic degenerative lesions of the lumbar spinal
    cord and nerve roots. All dose groups showed prominent and
    dose-related, pale mottled liver. Focal bile duct hyperplasia and
    biliary fibrosis, both in males and females; in addition some areas
    of focal cellular alterations were found. Focal bile duct
    hyperplasia occurred at incidence rates of 8%, 39%, 62% and 72% in
    males fed 0, 1, 3 and 6 mg/kg/day respectively and at rates of 8%,
    50%, 72% and 72% in females fed the same dosage of cyhexatin.
    Dose-related increases in relative weights (compared to body
    weights) of brain, heart, kidneys, pituitary, liver and spleen were
    found in males and/or females, the increases being significant for
    all organs at the highest dose group, for the brain and heart also

    1 purity: 98.6% uncorrected, 97.2% corrected; impurities: related
    tin compounds 2.9% and chlorine 0.1%.

    for the 3 mg group and, for the heart of females only, also at the 
    1 mg group. However, since the absolute organ weight changes were 
    generally decreases, the increased relative organ weights is a 
    reflection of the proportionately greater reduction in body weights 
    of the exposed groups. The tumor incidence was not increased (Warner 
    et al., 1977).

    Short-term studies

         Cyhexatin given to young male mice for 7 days at
    concentrations of 100 mg/kg diet gave a decrease in body weight of
    24%. Absolute weights of heart, liver and spleen were also
    decreased with 21, 32 and 61% respectively. Cyhexatin given to
    mature male mice for 4 days at concentrations of 30, 100 and 300
    mg/kg diet gave a decrease in body weight and relative weight of
    spleen at the highest dose group. A considerable decrease in the
    number of leucocytes was also found at this dose group (32% of
    control); on the other hand, a slight increase was noted in the
    level of haemoglobin, haematocrit and erythrocytes. All these
    effects were also present at 200 mg but less pronounced. There was
    no significant effect on the adrenal adrenalin level or on the
    percentage of dry matter of the brain (Ishaaya et al., 1976).


         Cyhexatin did not increase the number of benign or malignant
    tumors in a two-year rat feeding study with rats. Therefore the
    original finding of an increased incidence of liver adenomas in
    rats, could not be confirmed. However, the incidence of focal bile
    hyperplasia was increased in a dose-dependent fashion and was
    statistically significant at all dose levels (1,3 and 6 mg/kg),
    both in males and females. This was a more detailed study using
    more sophisticated methods than the study which was conducted 10
    years earlier. Since this study did not reveal a no toxic effect
    level, the previous indication that 3 mg/kg bw/day, causes no
    toxicological effects in rats was withdrawn. Further studies to
    elucidate the pathophysiological significance of focal bile
    hyperplasia are required before a firm ADI can be allocated.


    Level causing no toxicological effects

         Dog: level in the diet adjusted to give 0.75 mg/kg bw

    Estimated temporary acceptable daily intake for man

         0.008 mg/kg bw



    Crop use-outside USA

    Australia - cyhexatin is applied:

         (i)  to pome and stone fruits at 20g/100l (0.02%) concentration
              two or more times throughout the season, and a
              pre-harvest interval of 2 days in established;

         (ii) to strawberries at 20g/100l at 2-week intervals throughout
              the growing season, and a pre-harvest interval of 1 day
              is established;

         (iii) to various vegetables such as peas, beans, cucurbits at

    Netherlands - for the control of Red Spider mites

         (i)   to apples, pears, cherries (sweet and sour) and plums at a
               concentration of 25g/100l water, and a rate of 0.4-0.5
               kg/ha. The pre-harvest interval is 28 days.

         (ii)  to blackberries, raspberries, strawberries and red- and
               black currants at the same concentration and a rate of
               0.25-0.4 kg/ha. Spraying is carried out before
               blossoming and after harvest.

         (iii) to bell peppers, cucumbers, eggplants, gherkins, melons and
               tomatoes (glasshouse only) at the same concentration and
               application rate as (ii). The pre-harvest interval is 3

    South Africa - for the control of Red Spider mites cyhexatin is

         (i)   to apples and pears a concentration of 30 g ai/100l and a
               rate of 0.9-1.5 kg ai/ha. The per-harvest interval (PHI)
               is 3 days.

         (ii)  to peaches at 30g ai/100l and 0.75-0.9 kg ai/ha. The PHI is
               21 days.

         (iii) to plums at the rate of 30g ai/100l and 0.75-0.9 kg ai/ha.
               The PHI is 14 days.

         (iv)  to tomatoes at the rate of 0.38-0.45 kg ai/ha, with a PHI
               of 3 days.

    Livestock Use

         A wettable powder spray containing 500 mg cyhexatin per litre
    of water is applied in the following dosages; 3l per cow 1 1/2l per
    pig; 1l per goat; 1l per sheep (or dip in bath containing 250 mg

         The animals are treated totally. Repetition of the treatment
    after 8 days is mandatory to kill mites that have survived the
    previous treatment as eggs. No interval between treatment of cows
    and use of milk is specified.



         In trials by Dow Chemical (Australia) Ltd. before 1971,
    strawberries and beans were sprayed with cyhexatin. Strawberry
    plots on two sites were sprayed fourteen times with either one
    concentration (18.7g/100l or 0.02%) or two concentrations
    (18.7g/100l and 25g/100l or 0.025%) of cyhexatin. Samples were
    taken 0, 2, 4 and 10 days (Site 1) or 0, 5 and 10 days (Site 2)
    after the last treatment. Results are presented in Tables 1.

         Recovery tests carried out on the Site 1 samples gave 96% and
    101% for organic and total tin respectively. The average total tin
    values in strawberries, calculated as cyhexatin range from 0.43 to
    0.78 mg/kg for the 18.7 g/100l rate and 0.56 to 1.05 mg/kg for the
    25 g/100l rate.

         Beans were treated once with one concentration (20 g/100l or
    0.02%) cyhexatin and samples were taken four weeks after treatment.
    Results are presented in Table 1 section D. Tin residues in treated
    beans tour weeks after spraying did not differ significantly from

         In field trials in the Republic of South Africa apples, pears,
    peaches, plums and tomatoes were sprayed with cyhexatin and
    analysed for residues at various intervals after the last
    treatment. The results of these tests are presented in Table 2.


         To provide data in support of a proposed use of cyhexatin for
    the control of mange mites on sheep (Getzendaner et al., 1972)
    fifteen sheep were dipped twice in a vat containing 0.026% ai of a
    25% w.p. formulation, with 10 days between dips. Samples of tissues
    taken at slaughter 2, 7, 14, 28 and 60 days after the second dip
    were analysed for total tin. Essentially no residue was found in
    either omental or renal fat. Residues in muscle increased for 28

        TABLE 1. Tin residues on strawberries and beans (A, B, C refer to strawberries - D refers
             to beans)


                                                  Residue, mg/kg*
    Days                     Organic tin*                                 Total tin*
    After               As tin         As cyhexatin   Inorganic      As tin         As cyhexatin
    Application                                       tin

    A. Source:          Victorian Silvan.
       Application Rate:   18.7 g/100l

    Control             0.016                         0.024          0.040
    0                   0.190          0.617          0.013          0.203          0.660
    2                   0.082          0.266          0.067          0.149          0.480
    4                   0.070          0.227          0.076          0.146          0.470
    10                  0.044          0.143          0.090          0.134          0.430

    B. Source:          South Australia
       Application Rate:   18.7 g/100l

    Control             0.019          0.010          0.029
    0                   0.220          0.714          0.022          0.242          0.785
    5                   0.140          0.456          0.027          0.167          0.542
    10                  0.111          0.361          0.027          0.138          0.448

    C. Source:          South Australia
       Application Rate: 25 g/100l

    Control             0.019                                        0.029
    0                   0.268          0.927          0.036          0.322          1.045
    5                   0.160          0.518          0.048          0.208          0.675
    10                  0.107          0.346          0.072          0.179          0.558

    TABLE 1. (Cont'd)


                                                  Residue, mg/kg*
    Days                     Organic tin*                                 Total tin*
    After               As tin         As cyhexatin   Inorganic      As tin         As cyhexatin
    Application                                       tin

    D. Source:          N.S.W.
       Application Rate: 0.02% a.i.

    Control             0.028          0.07           -              0.048          0.15
    28                  0.031          0.10           -              0.050          0.16
    28                  0.015          0.05           -              0.015          0.05
    28                  0.030          0.08           -              0.036          0.12

    * Results corrected for control and recovery.

    TABLE 2. Tin residues on apple, pear, peach, plum and tomato


                                            Residues (mg/kg) at intervals (days) after last application
                             Number of                                                                                   
    Crop        Rate         Applications   
                                            0       1       2       3-4     7       14      16      21      28      29

    Apple       35g ai/100l       2                 1.23                                    0.54                    1.0
                "                 4                 1.04            0.83    0.73    0.67            0.50    0.59

    Pear        "                 1                         1.15                            0.49                    0.46
                "                 4                 0.9             0.7     0.76    0.64            0.41    0.43

    Peach       "                 1                 3.05                            1.09                    0.77
                "                 4                 3.33            3.88    3.74    2.58            1.81    1.11

    Plum        30g ai/100l       2                                         3.74    0.41            0.32

    Tomato      0.5 kg ai/ha      4         0.55    1.12    0.61    0.50    0.28    0.32
                1 kg ai/ha        1         1.86    1.75    1.15    1.05    0.52    0.66

    days to an average of 0.07 mg/kg of tin, then dropped to < 0.04 mg/kg. 
    The highest residue in liver was at two days after dipping averaging 
    0.07 mg/kg, dropping to < 0.04 mg/kg in 60 days. Kidney retained 
    about the same level of 0.06 to 0.09 mg/kg tin for 28 days, with 
    < 0.04 mg/kg after 60 days.

         In another experiment, nine pigs were treated with a 500 mg/kg
    spray to obtain information on residue levels of cyhexatin (Bant et
    al., 1977). The animals were slaughtered 3, 15 or 30 days after
    treatment and samples of diaphragm, liver, neck fat, neck skin and
    kidneys were analysed. It was found that 3 and 15 days after treatment
    the residues of cyhexatin in liver and kidney were just above the
    limit of detection (0.04 mg/kg cyhexatin). In muscle, fat and skin
    tissue, residues were below the limit of detection throughout the
    sampling period.


         One study has been conducted (Verschuuren, 1976) by the National
    Dairy Station, Leiden, Holland. Seven cows were treated twice, with a
    7-day interval between treatments, with 3l of spray containing 500 mg
    cyhexatin/l. Milk from the cows was analyzed for both organic and
    inorganic tin. The udders of 2 cows were washed before milking to
    eliminate potential environmental contamination. As shown in Table 3,
    the amounts of organotin and inorganic tin found in the milk are below
    or just above the limit of detection (0.002 mg/kg) with an average of
    0.003 mg/kg organic tin, and a maximum of 0.012 mg/kg. This is
    equivalent to 0.01 mg/kg average and 0.04 mg/kg maximum residue,
    calculated as cyhexatin.

         In another study (Hollick et al., 1978) three cows were treated
    twice with 31 of spray containing 500 mg/kg cyhexatin. Residues of
    organotin were determined after 1 or 2 days to investigate
    partitioning between butter fat and the aqueous phase. Residues in
    whole milk were below or just above the limit of detection (0.02 mg/kg
    as chyexatin), while after correction for control values mean residues
    in butter fat were 0.02 mg/kg or less (Table 7). Hence, under
    conditions of good veterinary practice, no real tendency has been
    shown for the cyhexatin residue to concentrate in fat. This indicates
    a need to revise the conclusions of the 1973 and 1975 Joint Meetings
    (FAO/WHO, 1974b, 1976b).

         The limit of detection depends on the quantity of the samples.
    For routine analysis in food control laboratories, limits of
    determination of 0.02 ppm for whole milk and 0.04 ppm for butter fat
    are reasonable.

        TABLE 3. Organotin residues in milk


    Cow                           Organotin (mg/kg as Sn) at intervals (days)
                                  after treatment

                                    7              8              8              9
                                  (p.m.)         (a.m.)         (p.m.)         (a.m.)

    1                             n.d.           0.009          n.d.           n.d.

    2                             n.d.           0.005          n.d.           0.012

    3                             0.006          0.008          n.d.           0.003

    4                             n.d.           0.005          n.d.           0.005

    5                             0.005          0.008          n.d.           n.d.

    6 (udder washed before
       milking)                   0.002          0.001

    7 (udder washed before
       milking)                   0.012          0.002

    n.d. = not detectable ( < 0.002 mg Sn/kg)

    TABLE 4. Organotin residues in milk following spray treatment of cows with cyhexatin

    Location                           : L.J. Boere, Holland

    Animal Breed                       : Friesian

    Treatment Data                     : Cattle were sprayed with 31 of a formulation
                                         containing 500 mg a.i./l i.e. 1.5 g ai/animal

    Treatment Dates                    : 7th February and 14th February 1978
    Cow            Day after      Organotin residue, mg/kg calculated as
                   treatment      cyhexatin 1) 2)
                                        Milk                    Butter
                                  Treated   Control        Treated   Control

    1              1              0.03-     <0.02          0.08-     0.04
                                  0.03                     0.04

    2              1              0.02-     <0.02          0.08-     0.04
                                  0.02                     0.04

    3              1              0.02-     0.02           0.06-     <0.04
                                  0.02                     0.04

    1              2              0.03-     -              <0.04-    -
                                  0.03                     <0.04

    2              2              0.03-     -              <0.04-    -
                                  0.02                     <0.04

    3              2              <0.02-    -              <0.04-    -
                                  <0.02                    <0.04

    1) Results not corrected for control or recovery.
    2) Cyhexatin mg/kg = corrected Sn mg/kg X 118.7; corrected tin is tin found minus
       reagent blank.

         In a 1975 market basket survey in Australia, canned peaches
    (among other commodities) were examined for contamination of the food
    contents by tin compounds. The total tin content ranged from 5 to 83
    mg/kg with the mean at 44.2 mg/kg, in the 72 samples examined. The
    analysis did not identify the tin compounds determined. The mean and
    range of tin residues found in canned peaches were of the same order
    of magnitude as were found for the other canned fruits examined, none
    of which had been sprayed with cyhexatin (as far as is known).
    Cyhexatin residues have not been reported, though not specifically
    sought, in raw produce (meaty grain, dairy products, fruit and
    vegetables) examined continuously in routine national surveys.


         There are no new methods of residue analysis to report, but a
    discussion of the residue analysed is appropriate.

    Definition of residue

         In the methods of analyzing crops or animals for residues on
    which national MRLs are established and on which the present
    recommended MRLs are based, all of the organic tin including cyhexatin
    and di- and mono- cyclohexyltin compounds are determined. This was
    recognized by the 1970 Joint Meeting (FAO/WHO, 1971b). However, in the
    recommendations for temporary MRLs the degradation products were
    excluded by the description of the residue, although in fact they are
    included by the methods of analysis.

         In the 1973 evaluations (FAO/WHO, 1974b), it was stated that
    practically all the organotin residue in oranges was present as
    cyhexatin. For tea leaves, all the data were for cyhexatin per se.
    Data on meat and milk were obtained by methods which determine total
    organic tin.

         In the 1974 evaluations (FAO/WHO, 1975 b), data are given on
    gherkins, cucumbers, bell peppers and tomatoes, all based on total tin

         To define the residues possibly present in the meat of animals
    consuming cyhexatin, Smith and Fischer (1970, cited in FAO/WHO, 1971b)
    determined that both cyhexatin and dicyclohexyltin oxide were present
    in the tissues of rats given cyhexatin -119Sn for 90 days, with the
    ratio of from 1:3 (dicyclohexyltin oxide:cyhexatin) 2 days after
    cessation of feeding cyhexatin, to 3:1 after 80 days. This was also
    true of rats fed cyhexatin for 2 years. (Anon. 1970a, cited in
    FAO/WHO, 1971b).

         Thus, a definition to cover all cases should include the
    cyclohexyltin and organic tin derivatives of cyhexatin, and the
    following definition is proposed.

    Definition (to apply to all post and future recommendations for MRLs
    for cyhexatin)

         Cyhexatin residue: cyhexatin and its organotin metabolites
    calculated as cyhexatin.


         New information was received from Australia, South Africa and the
    Netherlands, on maximum residue limits for cyhexatin in effect in
    those countries. These are:

    Australia      Stone fruits                  - 3 mg/kg
                   Strawberries                  - 3 mg/kg
                   Apples, pears                 - 2 mg/kg

    South Africa   Apples, pears                 - 2 mg/kg
                   Peaches                       - 2 mg/kg
                   Plums                         - 2 mg/kg
                   Tomatoes                      - 2 mg/kg

    Netherlands    Apples, cherries
                   (sour and sweet)
                   pears, plums                  - 1 mg/kg
                   Blackberries, raspberries,
                   red and black currants,
                   strawberries                  - 0.2 mg/kg
                   Gherkins                      - 1 mg/kg
                   Bell peppers, cucumbers,
                   melons, tomatoes              - 0.5 mg/kg


         A need for the direct application of cyhexatin sprays to dairy
    animals for the control of mites causing mange has necessitated a
    re-examination of residues in milk. Data were available from trials on
    dairy cows showing that, following recommended treatment practices,
    organotin residues in milk (and butter) were at or just about the
    limit of determination 0.02 mg/kg (0.04 butter) as cyhexatin 24 hours
    after the last treatment. In addition, the data provided evidence that
    accumulation of cyhexatin in butterfat did not occur. These new data
    are contrary to the interpretation reported in 1975 (WHO/FAO, 1976b)
    after re-examination of data presented in 1973 (WHO/FAO, 1974b). It is
    appropriate, therefore, to express the recommended limit on the basis
    of whole milk and milk products rather than on a fat basis. The
    previously recommended limit of 0.05 mg/kg (as cyhexatin) in milk is
    supported by the available data and because of the need for direct
    application to animals, the previous temporary extraneous residue
    limits (ERLs) for meat and milk should be converted to temporary MRLs.

         Data were available on residues of cyhexatin in tissues of sheep
    dipped twice at 10 day intervals in the miticide and on residues in
    meat of pigs sprayed once with a cyhexatin solution. These data did
    not indicate a need to revise the previously recommended temporary
    limit of 0.2 mg/kg in meat.

          Additional information was available to the Meeting on the use
    patterns and results of field trials on fruits and vegetables from
    Australia, the Netherlands and South Africa. Residue data from
    Australia indicate that residues on strawberries would not exceed 1
    mg/kg on the day of application and on beans would not exceed 0.2
    mg/kg by 28 days post-treatment. Residue data from South Africa on
    apples, pears, peaches, plums and tomatoes indicate that residues
    would not exceed 2 mg/kg on each commodity after the recommended
    pre-harvest interval.

         In the first evaluation of cyhexatin by the 1970 Joint Meeting,
    the recommendations for temporary maximum residue limits excluded the
    organotin degradation products although they are determined by the
    methods of analysis in use then and now. Subsequent reevaluations of
    cyhexatin did nothing to clarify the situation. Therefore, a
    definition of the residue is proposed which will cover those cases
    where cyhexatin is essentially the only residue and also those in
    which other organic derivatives of tin are present. This new
    definition does not require a change in the values of previously
    recommended limits.


         The following temporary maximum residue limits are in addition to
    those previously recommended except those for meat, milk and milk
    products which replace the extraneous residue limits previously
    recommended. The limits refer to cyhexatin and its organotin
    metabolites determined as total organic tin and expressed as
    cyhexatin. This definition applies also to all previous

              Commodity                             Temporary Maximum
                                                    Residue Limits, mg/kg

              Peaches, plums, strawberries          2

              Beans                                 0.5

              Meat                                  0.2

              Milk (whole), milk products (whole)   0.05


    Required by 1980

    1. Clarification of the no effect level in the rat with respect
    elucidating the significance of focal bile hyperplasia at low dose


    1.   A study to elucidate the possible effect on the immune system.


    Anonymous Information on cyhexatin from Australia.

    Anonymous Information on cyhexatin from South Africa.

    Bant, S., Braunius, W.W. and Hollick, C.B. Examination of pig
    (1977)         meat for the residue content of the anti-mange product
                   Dow Cyhexatin Miticide. Report provided by Dow
                   Chemical, Gouda, Holland.

    CCPR Report of the Tenth Session of the Codex Committee on Pesticide
    (1978)         Residues May 29 - June 5, 1978. Alinorm 79/24.

    Dow Chemical (Australia), Lt. Report No. 149. Plictran Residues in
    (1971)         Strawberries and Beans.

    Dow Chemical, USA. Information on use pattern for cyhexatin on dairy
    (1978)         animals and definition of a residue of cyhexatin.

    Getzendauer, M.E., Shover, R.J. and Corbin, H.B. A study of residues
    (1972)         of tin in tissues of sheep dipped twice in a vat
                   containing plictran R miticide. Report provided by the
                   Dow Chemical, U.S.A.

    Hollick, C.B., Braunius, W.W. and Iosson, D.I. Report of Dow Chemcial
    (1978)         Company, Ltd., Kings Lynn, England, GHE-A-204. Residues
                   of cyhexatin in milk and butter from cow treated with
                   cyhexatin miticides.

    Iahaaya, I., Engel, J.L. and Casida, J.E, Dietary triorganotins
    (1976)         affect lymphatic tissues and blood composition of mice.
                   Pestic. Biochem. and Physiol., 6: 270-279.

    Verschuuren, A.G. Report of Dow Chemical Europe, GHE-P-425. Residue
    (1976)         analysis of cyhexatin in milk after application on cows
                   following the recommended dose level. Report based on
                   data obtained from National Dairy Research Station,
                   Leiden. Netherlands. Original report in Dutch by Dr.
                   W.G. de Ruig.

    Warner S.D., Ayers, K.M. Gerbig, C.G. and Strebing, R.J. Results of
    (1977)         a two-year chronic toxicity study of tricylohexyltin
                   hydroxide administered to rats by the dietary route.
                   Unpublished report by Dow Chemical Co., U.S.A.

    WHO/FAO 1980 evaluations of some pesticide residues in food.

    WHO/FAO 1973 evaluations of some pesticide residues in food.

    WHO/FAO 1975 evaluations of some pesticide residues in food.

    See Also:
       Toxicological Abbreviations
       Cyhexatin (WHO Pesticide Residues Series 4)
       Cyhexatin (WHO Pesticide Residues Series 5)
       Cyhexatin (Pesticide residues in food: 1980 evaluations)
       Cyhexatin (Pesticide residues in food: 1981 evaluations)
       Cyhexatin (Pesticide residues in food: 1983 evaluations)
       Cyhexatin (Pesticide residues in food: 1989 evaluations Part II Toxicology)
       Cyhexatin (Pesticide residues in food: 1991 evaluations Part II Toxicology)
       Cyhexatin (JMPR Evaluations 2005 Part II Toxicological)