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    PESTICIDE RESIDUES IN FOOD - 1980


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1980





    Joint meeting of the
    FAO Panel of Experts on Pesticide Residues
    in Food and the Environment
    and the
    WHO Expert Group on Pesticide Residues
    Rome, 6-15 October 1980




    AMITRAZ

    IDENTITY

    Chemical Name (IUPAC): N-methylbis (2,4-xylyliminomethyl)
    methylamine

    Synonyms

    N,N-di-(2,4-xylyliminomethyl) methylamine
    2-methyl-1,3-di-(2,4-xlylimino)-2-azapropane
    1,5-di-(2,4-dimethylphenyl)-3-methyl-1,3,5-triazapenta-1,4-diene
    Daam(R), Mitac(R), Taktic(R), Triatox(R), BTS 27419, JA 119,
    U-36,059.

    Previously known as triazid or azaform.  In Chemical Abstracts
    usage it is:

    N'-(2,4-dimethylphenyl)-N-[(2,4-dimethylphenyl) imino]
    methyl]-N-methlylmethaniminamide [33089-61-1].

    Structural formula

    CHEMICAL STRUCTURE 1

    Molecular formula  C19H23N3

    Other information on identity and properties

    Molecular weight  293

    State             off-white crystalline solid

    Melting point     86-87C

    Vapour pressure   3.8  10-7 mm Hg at 20C

    Solubility        Less than 1 mg/l in water at room temperature;
                      readily soluble at room temperature in most
                      organic solvents, 666 g/l in xylene, 500 g/l in 
                      acetone, and 23.8 g/l in methanol.

    Stability

    Amitraz is a very weak base.  Potentiometric titration gives pK
    values of 4.0, 1.6 and 1.1, but the significance of the two lower
    figures is doubtful because the compound is unstable in acid
    solution, undergoing hydrolysis to yield ultimately
    2,4-dimethylformanilide (Table 1,III) and methylamine.

    Amitraz is relatively stable to heating, either alone or in a dry
    inert solvent such as xylene or toluene.  A xylene solution can be
    boiled for 7 days without detectable change and the pure material
    can be heated in air at 190C with only slight discolouration. 
    Methanolic solutions are unstable, but solutions in
    dimethylformamide or isopropanol are less so.

    A stream of oxygen has no effect when passed through a solution of
    amitraz in xylene at room temperature for 6 hours, but at reflux
    temperature some decomposition occurs.  A slow deterioration of the
    moist compound occurs on prolonged standing (Martin and Worthing,
    1979).

    Technical material

    The technical material is of a pale straw colour, and typically has
    a purity of 97-99% at the time of synthesis.  The minimum purity
    specified by the manufacturer is 93%.

    The principal impurity in the freshly manufactured product is
    NN'-bis(2,4-dimethylphenyl) formamidine (Table 1,VI)

    Storage stability of technical material

    Storage stability tests were carried out in 3 countries on
    technical amitraz stabilised with paraformaldehyde sachets inside
    sealed drums (Nix, 1979).  The results for the longest periods of
    storage may be summarised as follows:

                                                                        

    Country       Period       Mean loss of active    Content of
                of storage      ingredient (% of      (III) (%)
                                initial content)    Initial  Final
                                                                        

    Japan       24 months             Nil            <0.2     0.25
                plus travel
                to Japan and
                back

    Nigeria     22 months             4.4            <0.25    1.0
                plus travel                                   to
                to Nigeria                                    2.0
                and back

    Colombia    12 months              0.5            0.25    0.25
                plus travel                            to
                to Colombia                           0.50
                and back
                                                                        

    Formulations

    Amitraz is available as emulsifiable concentrates (200 g ai per
    litre for crop-protection, 125 g ai per litre for animal use) and
    wettable powders (500 or 250 g ai per kg).


    DATA CONSIDERED FOR DERIVATION OF ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, distribution, biotransformation and excretion

    In rats orally dosed with 14C-labelled amitraz recovery within 3
    days of the administration dose was 53-85% in urine, 17-47% in
    faeces, and <0.1% in expired air.  Peak plasma levels occurred
    about 1 hour after dosing.  Highest residues were found in liver,
    kidney and muscle after 0.75-1.5 hours, diminishing thereafter.  In
    urine at least 4 metabolites were found.  In faeces 6 metabolites
    were detected of which the major component was identified as BTS
    27271 (Lewis, 1971 a).

    During repeated oral dosing of 14C-labelled amitraz to rats highest
    residues were found in thyroid and adrenal glands, liver, skin,
    spleen and eyes.  After dosing ceased, a considerable decrease of
    residues was observed.  Radioactivity in blood was mainly cell
    bound.  Seven days after the final dose small but significant
    residues were detected in liver, spleen, skin and adrenals
    (Somerville, 1973 a).



        TABLE 1. Impurities Found In Technical Amitraz

                                                                                                             

              Chemical Name                 Referred to     Method of     Limit of    Typical      Specified
                                            in text as      Analysis      Detection   Content1       Limit
                                                                                                             

    a.  N-2,4-dimethylphenyl-N-
        methylformamidine

        "formamidine"                          (II)            TLC          0.2%      0-0.25%        2.0%

    CHEMICAL STRUCTURE 2

    b.  2,4-dimethylformanilide

        "formanilide"  "DMF"                   (III)           TLC          0.2%      0-0.25%        7.0% by
                                                                                                  difference

    CHEMICAL STRUCTURE 3

    TABLE 1. Continued...

                                                                                                             

              Chemical Name                 Referred to     Method of     Limit of    Typical      Specified
                                            in text as      Analysis      Detection   Content1       Limit
                                                                                                             

    c.  N,N'-bis-(2,4-dimethyl-phenyl)
        formamidine

        "diformamidine"                        (VI)            GLC          0.1%      0-3%           6.0%

    CHEMICAL STRUCTURE 4

    d.  2,4-dimethylaniline

        "xylidine"  (DMA)                      (IV)            TLC          0.05      0-0.1%         0.3%

    CHEMICAL STRUCTURE 5

    TABLE 1. Continued...

                                                                                                             

              Chemical Name                 Referred to     Method of     Limit of    Typical      Specified
                                            in text as      Analysis      Detection   Content1       Limit
                                                                                                             

    e.  1,3,5-tri-(2,4-dimethyl-phenyl)

        -1,3,5-triazapenta-1-4-diene           (VII)           GLC          0.2%      0-0.25%        2.0%

    CHEMICAL STRUCTURE 6

    f.  N,N'-bis-2,4-dimethyl-phenyl

        -N-methyl formamidine                 (VIII)           GLC          0.1%      0-0.25%        2.0%

    CHEMICAL STRUCTURE 7

    TABLE 1. Continued...

                                                                                                             

              Chemical Name                 Referred to     Method of     Limit of    Typical      Specified
                                            in text as      Analysis      Detection   Content1       Limit
                                                                                                             

    g.  Ethyl-N-2,4-dimethyl-phenyl
        formimidate

        "formimidate"                          (IX)            TLC          0.5%      0-0.5%         2.0%

    CHEMICAL STRUCTURE 8

                                                                                                             

    1 Typical Content specifically refers to freshly manufactured material
    


    Twenty-four hours after dermal application of labelled amitraz in
    acetone solution to rats approximately 50% of the dose had been
    excreted in urine and faeces (Lewis, 1971 b).

    Ninety-six hours after a single oral dose of 14C-labelled amitraz to
    dogs the recovery in the excreta was 81% (57% in urine and 24% in
    faeces).  The peak plasma levels varied between 1.5 and 6 hours after
    dosing for the male and the female dog respectively (Lewis, 1971 c).
    One to four days after dosing significant residues were found in
    liver, kidney, skin, bile and the pigmented tissue of the eye (iris,
    retina and choroid and sclera) (Lewis, 1971 c; Hamilton and
    Somerville, 1974 a).

    In calf and mice a similar pattern of distribution and elimination of
    radioactivity was observed after oral treatment with 14C-ring
    labelled amitraz (Somerville, 1973 b; Hamilton, 1976).

    A lactating cow was treated dermally twice with a 7-day interval with
    14C-amitraz.  In milk the maximal concentration of radioactivity was
    0.09 ml/l.  Nine days after the second application the concentration
    was 0.03 mg/l (Somerville, 1972).

    Metabolites of labelled amitraz measured in liver and urine showed
    similar patterns for all species examined, i.e. rat, mouse, dog, cat
    and calf.  At least 6 metabolites were present of which conjugates of
    3-methyl-4-amino-benzoic acid (BTS 28369) were predominant.  In urine
    of dogs and rats a difference in number and type of metabolites
    between males and females was found (Jones, 1973 c).

    The proposed metabolic pathway is given in figure 1.

    In vivo and in vitro degradation studies in dog gastric juice of
    amitraz revealed rapid hydrolysis to BTS 27271, BTS 27919 and BTS
    24868 (Somerville and Hughes, 1973 e; Taylor and Somerville, 1977).

    Administration of BTS 27271 to cats and dogs resulted in a similar
    distribution pattern and metabolic degradation as was observed for
    amitraz (Jones, 1973 d; Hamilton and Somerville, 1973; Hamilton and
    Somerville, 1974 c).

    From accumulation-elimination studies of BTS 27271 in dogs the half
    lives in retina/choroid and the iris were estimated to be 1.5 and 3
    days respectively (Somerville and Hamilton, 1974).

    2,4-Xylidine (BTS 24868) administered to rats predominantly oxidized
    to 3-methyl-4-amino-benzoic acid (BTS 28369).  This metabolite is
    excreted as the acetanilide conjugate (Lindstrom, 1961).

    3-methyl-4-amino-benzoic acid (BTS 28369) administered in a single
    oral dose to dogs gives significant residues in iris, liver and skin,
    24 hours after dosing.  The excretion of the compound was maximal in
    the first 7 hours (Hamilton and Somerville, 1974 b).

    FIGURE 1

    TOXICOLOGICAL STUDIES

    Special Studies on Reproduction

    Effect of amitraz on the oestrous cycle

    In female SFP CFLP mice fed a diet containing 400 mg amitraz/kg feed
    for up to 33 weeks a reduction in body weight and an increase in food
    consumption was observed.  Analysis of vaginal smears indicated that
    the mean duration of oestrus as well as the incidence of a prolonged
    oestrus was significantly increased due to treatment.  No effects were
    found on the level of -oestradiol in plasma (Brown et al, 1978;
    Channon and Cryer, 1978).

    Female rats maintained on a diet containing 200 mg amitraz/kg for 18
    weeks had longer oestrus cycles than control rats of the same age,
    resulting from prolonged periods of oestrus or dioestrus (Merryman and
    Sutton, 1972).

    Effect on pregnancy, parturation and care of the young

    Amitraz was administered in doses of 0, 1, 3 or 12 mg/kg bw to
    Boots-Wistar rats from day 1 of pregnancy until the young were weaned
    at 21 days old.  12 mg/kg bw reduced the weight gain of the dams as
    well as the mean number of young born and alive at day 4.  No effects
    were observed for mothers and offspring for the other dose groups
    (Sutton, 1973 c).

    Three-generation feeding study

    Groups of 10 male and 20 female newly-weaned Boots-Wistar rats were
    fed amitraz in dietary concentrations of 0, 15, 50 or 200 mg/kg. 
    After ten weeks the animals were mated.  After the F1 generation was
    weaned 12 males and 24 females from each group were retained for
    breeding and maintained on the diet.  The procedure was repeated until
    the F3 generation was weaned.  At 200 mg/kg amitraz causes decrease
    of growth and food consumption in the F0 generation, furthermore a
    decrease in fertility and viability was found.  The 200 mg/kg diet
    group was terminated when the F1 generation was weaned, due to the
    very low survival.  In the 50 mg/kg group no effect was found on the
    number of litters and mean litter size, however in all generations a
    decrease in number of young alive at 21 days was observed.  No further
    effects due to treatment were found in this and the other dose group
    (Sutton, 1973 d; Lancaster and Williams, 1978).

    Special Studies on teratogenicity

    Rat

    Groups of 11-13 female rats received amitraz in doses of 0, 1, 3 or 12
    mg/kg bw daily from day 8 to day 20 of pregnancy.  The rate were
    killed on day 21 and the uterine content was examined.  Average litter
    size, foetal viability and implantation index were not affected.  In
    the highest dose group foetal weight was less than in the controls,
    and the calcification of the stermebrae was less advanced (Sutton,
    1973 b).

    Rabbit

    Groups of 8-10 New Zealand rabbits were treated with amitraz in doses
    of 0, 1, 5 or 25 mg/kg bw from day 6 to 18 of pregnancy and killed on
    day 30.  In the highest dose group number of litters and mean litter
    size were decreased.  Only in this dose group abortions were observed.
    No increase in congenital abnormalities was found (Sutton, 1973 a).

    Special studies on mutagenicity

    Bacterial systems

    Amitraz and its major metabolites (BTS 27271, 27919, 28369) were
    tested in bacterial in vitro systems, with and without activation,
    against Salmonella typhimurium TA 1535, 1437, and 1538 and
    Escherichia coli Wp2 and Wp2 uvrA.  In these systems no mutagenic
    activity was detected (Everest and Wilcox, 1976 a, 1976 b; Tuplin and
    Wilcox, 1978).

    The impurity BTS 33220 (N,N'-bis-2,4-dimethylphenyl-N-methyl
    formamidine) showed weak positive activity against TA 100 in the
    presence of microsomes.  Amitraz spiked with 1% BTS 33220, however,
    did not show any mutagenic action (Wilcox, 1979; Everest and Wilcox,
    1979).

    In the TA 100 strain BTS 24868 and BTS 27919 exhibited weak but
    consistent mutagenic activity (Zimmer at al, 1977).

    Amitraz showed no increase in point mutational activity against
    Salmonella typhimurium G 46, TA 1532 and TA 1964 when tested in
    the mouse perivisceral host-mediated assay at single oral doses up to
    400 mg/kg bw (Wilcox, 1976; Everest, 1976).

    Dominant Lethal Studies

    Female mouse

    Groups of 48 female mice were treated orally for 5 consecutive days
    with amitraz in doses of 0, 12 or 50 mg/kg bw.

    Subgroups of 12 females were mated with untreated males on day 3, 9,
    14 or 19 post-dosing.  A slight increase in mean post-implantation
    loss and decrease in mean viable litter size at 50 mg/kg was found
    (Palmer and James, 1977 a).

    Male mouse

    Male mice of proven fertility were treated with amitraz for 5
    consecutive days at doses of 0, 12 or 50 mg/kg.  Following treatment
    males were mated with untreated females for six consecutive weeks.  A
    significantly lower implantation rate was found at 50 mg/kg at the
    first mating and a higher implantation rate at 12 mg/kg at the 5th
    mating.  No changes were found in respect to number of embryonic
    deaths and post implantation losses (Palmer and James, 1977 b).

    DNA damage

    Amitraz, BTS 27271, 27919, 24868 and 28369 were tested at several dose
    levels in the DNA damage/alkaline elution assay with or without
    activation systems, using chinese hamster lung fibroblasts.  In this
    test system no indication was obtained that amitraz or its metabolites
    induce DNA damage (Petzold et al, 1977).

    Special studies on carcinogenicity

    Mouse

    Groups of 50 male and 50 female mice (CFLP strain) were fed a diet
    containing 0, 25, 100 or 400 mg/kg for 80 weeks.  The animals of the
    100 and 400 mg/kg diet groups gained less weight than the control over
    the first 40 weeks.  The 25 mg/kg diet group gained more weight than
    the control group from week 10 onwards and showed a 20% greater body
    weight gain at the end of the experiment.  Calculated over 80 weeks,
    food consumption was increased for male mice at 100 and 400 mg/kg diet
    and decreased at 25 and 100 mg/kg diet and increased at 400 mg/kg diet
    for female mice.  The survival rate was similar in all groups.  An
    increased incidence of lymphoreticular tumours was observed for female
    mice at 400 mg/kg only; 49% compared with 23% in control animals.  A
    slight, although not statistically significant (p>5%) increase of all
    types of liver cell tumours was found in both sexes fed 400 mg/kg.  No
    other pathological findings related to treatment were reported
    (Burnett et al, 1976; Kakuk 1979).

    Rat

    Amitraz was administered at dietary concentrations of 0, 15, 50 or 200
    mg/kg to groups of 40 male and 40 female Ash Wistar rats for 2 years.
    Due to treatment in the highest dose group the animals tended to be
    nervous, aggressive and excitable.  In this group growth rate was
    depressed for both sexes and food intake was slightly less in the
    first weeks of the experiment.  No dose-related anomalies were found
    on organ weights and haematological, biochemical and histopathological

    examination.  Furthermore, no difference in incidence, type and time
    of appearance of tumours in control and treated rats was observed
    (Sutton and Offer, 1973).

    2,4-Xylidine carcinogenicity study

    Mouse

    2,4-Xylidine (BTS 24868) was fed in the diet of 3 groups of HAM/ICR
    mice (25 males and 25 females) in a concentration of 0, 1000 or 2000
    mg/kg.  Since these doses were not tolerated the experiment was run
    again with doses of 0, 125 or 250 mg/kg diet.  Dosing was
    discontinuated after 18 months.  After 24 months the animals were
    killed and examined for tumours.  In female mice an increased
    incidence of lung tumours was observed in the highest dose group (NCI,
    1973).

    Rat

    2,4-Xylidine (BTS 24868) was administered to groups of 25 male Charles
    River rats for approximately 3 months at doses of 2000 or 4000 mg/kg
    diet; thereafter the doses were changed to 0, 250 or 500 mg/kg diet
    respectively, for approximately 2.5 months and subsequently, the doses
    were set at 0, 500 or 1000 mg for the rest of the 18 months period.
    At that time the feeding of the test compound was discontinued until
    sacrifice 24 months after starting the experiment.  A slight increase
    in lung tumours in the highest dose group was observed.  Furthermore
    in the treated groups bladder and liver tumours were observed,
    which were not found in the controls (NCI, 1973).  However, in
    contrast to their earlier conclusions, the authors finally stated that
    there was no carcinogenic effect in the rat (Weisburger et al,
    1978).

    Special studies on pharmacological effects

    In dogs amitraz and BTS 27271 produce similar effects when given
    orally in doses of 4, and 0.5 mg/kg bw respectively either after
    single or repeated administration.  Signs included sedation, ataxia,
    protrusion of the tongue, bradycardia and hypothermia (Morgan et al,
    1975 b).

    An experiment comparing oral and topical application of amitraz in
    pigs revealed a decrease in rectal temperature after oral dosing (25
    mg/kg bw and higher), whereas no effects were found after topical
    application up to 200 mg/kg bw (Morgan et al, 1975 a).

    No flushing could be demonstrated in pigs after topical or
    intramuscular administration of amitraz and BTS 27271 although other
    pharmacological changes were apparent (Parkinson, 1975).

    Amitraz and BTS 27271 did not have any effect on trafuril-induced or
    UV-induced erythema in the guinea pig (Patton, 1970; Parkinson and
    Yates, 1971).

    BTS 27271 was antidiuretic in mice at 90 mg/kg bw whereas amitraz in
    the same dose was ineffective (Sim, 1970).

    Intravenous administration of amitraz caused vasoconstriction in the
    ear vessels of cats (1-10 g/kg) and fall in blood pressure and
    bradycardia (>20 g/kg) in dogs.  BTS 27271 evoked similar effects in
    dogs (40 g/kg).  Both compounds had no effect on the response of the
    blood vessels of the rabbit ear to antidromic stimulation or to
    catecholamines (Anonymous, 1972; Parkinson et al, 1971 a; Parkinson
    et al 1971 b; Patton, 1973 b).

    Amitraz induced hypothermia in mice under various ambient conditions.
    This effect was greater in intensity and duration in females (Sutton,
    1972 a; Berry, 1976).

    BTS 27419, BTS 27271 and BTS 21103 were tested for their potency of
    central monoamine oxidase inhibition in mice and rats, by
    investigating the influence on reserpine-induced ptosis and inhibition
    of exploratory activity.  No effects were observed in mice.  At high
    doses these compounds antogonise reserpine-induced ptosis in the rat,
    suggesting a relative potency in the order BTS 27271 > BTS 27419 >
    BTS 21103 (Parkinson, 1974 a).

    BTS 27419, BTS 27271 and BTS 21103 potentiated the pressor response to
    tyramine in the pithed rat at doses of 40, 80 and 80 mg/kg bw
    respectively.  Similar effects have been shown with monoamine oxidases
    inhibitors (Parkinson, 1974 b).

    Special studies on sensitisation and irritation

    Neither amitraz nor BTS 27271 showed sensitisation activity in guinea
    pigs (Sutton, 1971).

    Amitraz was not irritant to the rabbit eye after a single
    administration (Sutton and Metcalf, 1972).

    Acute toxicity

    Acute oral administration of amitraz caused CNS depression in all
    species studied.  Dogs were more susceptible than the others.  Toxic
    manifestations: ataxia, subnormal rectal temperature and
    cardiovascular disturbance.

        TABLE 2.  Acute Toxicity of Amitraz

                                                                                         

    Species     Sex    Number      Route      LD50 (mg/kg)      Reference

                                                                                         
    mouse        M       5         oral          >1600          Patton and Sutton, 1971

    rat          M       5         oral       approx. 800       Patton and Sutton, 1971
                                                                Shaw, 1973a

    rat          M       5         i.p.       approx. 800       Shaw, 1971, 1973a

    rat         M,F      6       inhalation     (6 h LC50)      Berczy et al, 1972
                                                65 mg/kg

    rat          M       5        dermal         > 1600         Patton and Sutton, 1971

    guinea pig   F       3         oral          400-800        Patton and Sutton, 1971
                                                                Sutton 1970c

    rabbit       F       2         oral          > 100          Patton and Sutton, 1971

    rabbit      M,F               dermal         > 200          Sutton and Williams, 1972

    dog         M,F      2         oral       approx. 100       Patton and Sutton, 1971

    baboon      M,F      2         oral         100-250         Patton, 1973a
                                                                                         
    
    BTS 27271 is more toxic than amitraz.  Signs of poisoning are similar
    to those shown by amitraz.  A summary of acute toxicity data of
    impurities degradation products and metabolites of amitraz is given in
    table 3.

    Short-term studies

    Mouse

    Groups of 10 male and 10 female CFLP-mice (age 4 weeks) were dosed
    with 3, 12, 50 or 200 mg/kg/day amitraz by gavage (suspended in 0.4%
    cellosize; 0.1 ml/10 g bw) for 90 days.  Control groups of 20 males
    and females received the same volume of vehicle alone.

    Eight mice (5 males and 3 females) given 200 mg/kg/day died within 3
    weeks after becoming progressively emaciated and inactive.  The
    surviving animals of this group were in poor condition.  In the other
    groups 5 animals died of causes probably not related to treatment. 
    The 50 and 200 mg/kg groups showed a decreased body weight gain over
    the experimental period for both sexes.  The body weight gain of male 




        TABLE 3. Acute Toxicity of Impurities, Degradation Products and Metabolites of Amitraz

                                                                                                              
    compound    species     number   route   LD50 (mg/kg)        vehicle          references

                                                                                                              
    BTS 27271   mouse         5      oral      100-200       HCl salt aq. sol.    Sutton, 1970a
                rat           5      oral          200       idem                 Sutton, 1970b
                guinea pig    3      oral          200       idem                 Sutton, 1970c
                dog           2      oral          >20       gelatin capsules     Morgan, 1973a
                                                                                  Morgan and Williams, 1973a
                rabbit        2      oral          >25       HCl salt aq. sol.    Sutton, 1972b

    BTS 27919   mouse         5      oral        >1600       idem                 Anonymous, 1971a
                rat           4      oral    approx. 1600    idem                 Shaw, 1973b
                dog           2      oral         >100       gelatin capsules     Morgan, 1974a
                                                                                  Morgan and Turnhull, 1973

    BTS 28369   dog           2      oral         >250       idem                 Morgan and Sheperd, 1974
                                                                                  Morgan 1974b

    BTS 24868   mouse         5      oral          800       -                    Anonymous, 1971a

    BTS 33220   rat           5      oral     800-1600       10% acacia mucilage  O'Donovan and Smithson, 1978

    BTS 28037   dog           2      oral         >250       gelatin capsules     Morgan, 1973b
                                                                                  Morgan and Williams, 1973b
                                                                                                              
    

    and female mice of the 3 and 12 mg/kg groups was slightly decreased. 
    GPT activity increased in both sexes from 50 mg/kg.  Male mice showed
    a slight increase in haematocrit at 3 and 12 mg/kg.  Reducing
    substances in blood were found to be decreased in both sexes at 12 and
    50 mg/kg.  Organ weight/body weight ratio of the kidney was increased
    in males from 12 mg/kg; of the liver increased for both sexes at 50
    and 200 mg/kg and of the spleen for males at 50 and 200 mg/kg and for
    females at 200 mg/ kg only.

    Slight to moderate hepatocyte and/or nuclear enlargement was observed
    dose-relatedly at 12, 50 and 200 mg/kg.  Furthermore, in the liver of
    some females of the highest dose group, intranuclear inclusion, bile
    duct proliferation and inflammatory infiltration in the portal tracts
    and nodular hyperplasia were observed (Shaw and Williams, 1974).

    Four groups of 13 female and 13 male ICR-SLC mice received amitraz in
    doses of 0, 3, 12 or 50 mg/kg bw, in the diet (presuming that the
    daily consumption was 5 g/animal) for 90 days.  Six males died at an
    early stage of the experiment.  According to the authors death was not
    due to treatment.  In both sexes growth was depressed in the 12 and 50
    mg/kg groups.  Food and water intake were slightly decreased at 12 and
    50 mg/kg; for males this was more pronounced than for females.  In
    male mice a slight decrease in food efficiency was observed at 50
    mg/kg over the whole experimental period.  For male mice relative
    brain weight was increased at 50 mg/kg and heart weight at 12 and 50
    mg/kg.  The relative kidney weight of female mice at 50 mg/kg was
    decreased.  SGPT and aldaline-phosphatase were decreased whereas the 
    albumin-globulin ratio was increased in female mice of the two highest
    dose groups.  Male mice only showed a higher albumin-globulin ratio at
    50 mg/kg.  At the end of the experiment macroscopically slight black
    discolouration of the liver was seen predominantly in the highest dose
    group.  The only histopathological change probably directly related to
    the administration of the compound was a slight centrolobular
    degeneration in the liver at 3, 12 and 50 mg/kg (Toyoshima et al,
    1972 b).

    Rat (inhalation)

    Three groups of 6 female and 6 male rats were exposed daily for six
    hours to amitraz at concentrations of 0.01, 0.1 or 1.0 mg/l air
    respectively for 14 days over a period of three weeks.  During
    exposure to 0.1 mg/l dyspnoea, eye-irritation and hyposensitivity to
    noise were observed.  In addition at 1.0 mg/l ataxia, increased nasal
    secretion, polyuria, body tremors and slight coma were found.  Body
    weight gain was markedly reduced in both sexes at 0.1 and 1.0 mg/l
    air.  Haematological studies revealed a decreased PCV, haemoglobin and
    red blood cell count and increased number of neutrophils in both sexes
    and a decreased NCHC and number of lymphocytes in males of the highest
    dose group (no other groups examined).  At 0.1 and 1.0 mg/l
    significant alterations of the relative weights of brain, kidney,
    thyroid and adrenal glands, and gonads were found for males, and of
    brain, kidney and adrenals of female rats.  Liver, heart and pituitary
    for males and liver for females were increased in the highest dose

    group only.  No pathological findings related to treatment were found
    (Berozy et al 1973).

    [text missing] abnormalities, dosing was restarted for 1 week in which
    toxic reactions returned.  Rats of the 12 mg/kg group appeared
    irritable and excitable.  In male rats body weight gain was depressed. 
    A significantly depressed relative liver weight was seen at 50, 12 as
    well as 3 mg/kg for males but only at 50 mg/kg for females.
    Alkaline-phosphatase activity was decreased at 50 and 12 mg/kg (Sutton
    and Williams, 1971).

    Rat

    Groups of 10 Wistar rats of each sex received amitraz in doses of 0,
    3, 12 or 50 mg/kg bw in the diet (presuming the daily food consumption
    was 20 g/animal) for 90 days.  Body weight gain was decreased in the
    50 mg/kg group for both sexes and in the 12 mg/kg group for females
    only.  Food and water consumption were decreased in all dose groups.
    The relative weight of brain, heart, lung, liver, kidney, spleen and
    uterus or testes were increased for both sexes in the highest dose
    group.  In addition the adrenals were decreased and thymus was
    increased in weight in male rats of the highest dose group.  Male rats
    showed a dose-related decrease in number of blood platelets in the 12
    and 50 mg/kg group.  Female rats showed a significant decrease in
    eosinophils in the highest dose group.  In serum of male rate of the
    highest dose group a decrease was observed in the Alk Pase activity
    and blood sugar concentration, and an increased serum potassium
    concentration.  Urinalysis revealed an increased number of rats with
    proteinurea from the 12 mg/kg group onwards.  In male rate urine
    potassium concentration was significantly decreased at 12 and 50
    mg/kg, in females only at 50 mg/kg (Toyoshima et al, 1972 a).

    Rabbit (dermal)

    Amitraz dissolved in acetone was applied to the intact skin of groups
    of New Zealand rabbits (4 males and 4 females) in 15 doses of 0, 50 or
    200 mg/kg bw over a 2l-day period.  One male and three females at 200
    mg/kg and one male at 50 mg/kg died intercurrently.  Sedation was
    observed in males at 50 mg/kg and in both sexes at 200 mg/kg.  In
    males of both dose groups slight to moderate erythema, desquamation of
    skin and subcutaneous hemorrhage were observed.  In both sexes
    decreased body weight and food consumption were found in the 50 and
    200 mg/kg dose groups.  In males at 200 mg/kg underweight testes with
    tubular degeneration were found (Sutton, 1973 e).

    Dog

    Amitraz in gelatine capsules was given to groups of two male and two
    female beagle dogs in oral doses of 0, 0.25, 1 or 4 mg/kg once daily
    for 90 days.  Clinical signs were observed in all dosed groups
    consisting of CNS depression, ataxia and vomiting during the first
    days within 3-6 hours after dosing.  These dogs were subdued
    throughout the experimental period.  When examined at intervals during

    the treatment period the dogs consistently had subnormal rectal
    temperatures and pulse rates.  These parameters returned to normal
    within 6-24 hours after administration.  The animals of the 1 and 4
    mg/kg dose groups showed a significant increase in blood sugar
    concentration which was maximal 6 hours after dosing and returned to
    normal within 24 hours.  In the same dose groups an increased amount
    of glucose and total reducing substances was found in the urine in
    weeks 2 and 3.  In the highest dose group an increased liver weight
    was observed in both sexes.  Except in control animals, livers showed
    enlargement of the central and midzonal hepatocytes.  Hyperplasia of
    the small periportal hepatocytes and increase in binucleate cells were
    particularly evident in the highest dose group.  At all dose levels
    thinning of the zonae fasciculata and reticularis, sometimes
    associated with slight hyperplasia of the zona glomerulosa in the
    adrenales, was observed (Patton and Williams, 1971).

    Metabolites

    Rat (90-day test with BTS 27271)

    Groups of 10 male and 10 female Boots-Wistar rats were dosed orally by
    gastric intubation with BTS 27271 for 90 days at doses of 0.25, 1, 3
    or 12 mg/kg bw/day.  In the 12 mg/kg group the rats were nervous and
    difficult to handle.  Body weight was slightly lower at 3 and 12 mg/kg
    compared to the controls, the males being more affected than the
    females.  At the end of the experiment the number of erythrocytes was
    decreased in the 3 and 12 mg/kg group for females and in the 12 mg/kg
    group for males.  Haemoglobin and haematocrit values were decreased at
    12 mg/kg for males only.  Owing to the variation in the number of
    lymphocytes the leucocyte counts were decreased for male and increased
    for female rats in the highest dose group.  Concomitantly a
    significant decrease in number of eosinophils was found.  Urinalysis
    revealed an increased GPT activity in females, and a slight increase
    in urine volume and decrease in specific gravity in the males of the
    highest dose group.  Together with these changes an increase in BUN
    was found.  In terminal plasma samples a significant increase in
    alkaline-phosphatase activity in both sexes given 12mg/kg was found.
    The relative weights of adrenals, ovaries and uterus in the females
    and the testes in the males given 3 and 12 mg/kg were increased.  In
    the highest dose group the weight of liver for females and spleen for
    males was increased.  Microscopic examination of rats given 3 or 12
    mg/kg showed a slight increase in lymphoid infiltration with some
    leucocytosis and a loss of glycogen in the liver (livers of female
    rats were not examined at 3 mg/kg).  In the highest dose group the
    hearts of the female rats showed slight cellular accumulation (Shaw
    and Williams, 1975).

    Dog (90-day test with BTS 27271)

    Groups of 4 male and 4 female beagle dogs were given 0, 0.1, 0.25 or 1
    mg BTS 27271/kg bw in gelatin capsules daily for three months.  The
    test compound was diluted in lactose to 1% BTS 27271 as free base.

    Clinical signs in the 0.25 and 1 mg/kg group were abnormal quietness
    and drowsiness.  Between 1 and 4 hours after dosing the mean body
    temperature and mean heart rates decreased significantly for the 0.25
    and 1 mg/kg dose groups.  In the highest dose group a significant
    increase in liver weight was found.  A slight reduction in thymus
    weight was observed at 0.25 and 1 mg/kg.  In the highest dose group
    the urine volume was found to be increased.  No histopathological
    anomalies were found (Chesterman et al, 1973).

    Rat (21-day test with BTS 28369)

    BTS 28369 was administered orally to groups of 4-6 male and female
    rate (Boots-Wistar) at dose levels of 0, 40, 100 or 250 mg/kg bw/day
    for 21 days.  In the highest dose group a slightly decreased weight
    gain and BUN level was observed for males and an increased relative
    weight of the spleen for females.  No pathological changes due to
    treatment were found (Shaw, 1975).

    Dog (90-day test with BTS 28369)

    Groups of 4 male and 4 female beagle dogs were dosed 0, 16, 40 or 100
    mg BTS 28369/kg bw/day orally in gelatin capsules for 90 days.  At 100
    mg/kg bw slightly elevated urinary levels of total reducing substances
    were found.  No dose related effects were observed on behaviour, ECG,
    heart rate, rectal temperature, body weight, food consumption,
    haematology, blood biochemistry, organ weights and histopathology
    (Morgan et al 1974).

    Long-term studies

    Rat

    See under "Special studies on carcinogenicity".

    Dog (2 years)

    Groups of 4 male and 4 female beagle dogs were given 0, 0.1, 0.25 or 1
    mg amitraz/kg bw/day orally in gelatin capsules for 2 years.  Three
    hours after dosing all dogs given 1 mg/kg bw exhibited CNS depression
    on day 1 and 2, blood sugar level was slightly increased at weeks 40
    and 53 (the only weeks measured).  No effects on haematological,
    biochemical and histopathological parameters were reported (Morgan
    et al, 1973).


    OBSERVATIONS IN HUMANS

    After a few complaints from people involved with the development of
    amitraz, all workers in this department were interviewed by the
    medical staff, which led to the following conclusions:

    1) Skin flushing due to capillary dilatation may be caused by amitraz
    or its precursor BTS 27271, or both.

    2) The response appears to be the result of systemic absorption rather
    than topical application.
    3) Absorption is more likely to occur when large quantities are
    processed.  So far skin effects have not followed the use of
    formulated materials in the course of animal or crop protection
    trials.

    4) Apart from the observation that the capillary circulation in the
    skin appears to have been sensitised to trauma such as gentle friction
    and radiant heat, no other information can be offered to explain the
    phenomena described.
    5) The effects appear to be temporary and disappear soon after contact
    with the materials is discontinued (Moore, 1972).

    Amitraz (about 10 mg) was applied to the arms of 9 volunteers as 0.02
    ml of a 50% acetone solution.  After 6 hours the arms were cleaned.
    One volunteer, who had previously reacted to the compound, showed a
    slight erythema localized to the patch area.  
    Three volunteers who had previously reacted to this compound were
    tested using a single application of a paraffin-based ointment
    containing 50% amitraz.  One subject reported a delayed reaction
    occurring 14 h after the initial application consisting of a reddening
    of his previous reaction to this compound; no throbbing or other
    symptomatology was observed and the reaction had faded by the morning
    (Anonymous, 1971 b and c).

    Six volunteers received a single oral dose of 2 mg BTS 27271 in a
    double-blind crossover study.  Blood pressure, pulse rate and oral
    temperature were different comparing the volunteers receiving the
    active treatment to those receiving placebo.  This difference existed
    just as much initially as during the observation period.  Mental
    alertness scores show that a number of subjects felt relatively more
    alert on placebo (Hall et al, 1975).

    In urine of production workers and volunteers the expected terminal
    metabolite, BTS 28369 could be detected (Shirley, 1975 b, 1976;
    Hughes, 1975).


    RESIDUES IN FOOD

    USE PATTERN

    Amitraz is used for the control of pests on both animals and crops and
    is used in countries throughout the world as an insecticide and
    acaricide.

    Treatment of crops

    As an acaricide, amitraz is successfully used against red spider mites
    on deciduous fruit crops, citrus, cotton and certain other crops.  As
    an insecticide it is used to control pear psylla and whitefly, and as
    an ovicide against the major cotton lepidopterous pests.

    Recommendations for its use on cotton, deciduous top fruit, citrus,
    ornamentals and vegetables are shown in Tables 4 and 5.

    Treatment of animals

    Amitraz is effective against ticks, mange mites, lice and keds on
    cattle, sheep, goats and pigs (Tables 6 and 7).
    The species of skin parasites controlled by amitraz are shown in Table
    8.



        TABLE 4. Use Pattern on Crops

                                                                                                                                              
                                                                                                           APPLICATION RATES
    CROP                PEST                             TIMING                                   High Volume                Low Volume
                                                                                             g a.i./hl   litres          g a.i./ha   litres
                                                                                                         AMITRAZ 20% EC              AMITRAZ
                                                                                                         1000 l water                20% EC/ha
                                                                                                                                              
    COTTON              Lepidoptera
                        Cotton Bollworm
                        Heliothis spp.
                        Pink Bollworm
                        Pectinophora gossypiella
                        Red (Sudan) Bollworm
                        Diparopsis castanea              Spray when eggs first                                            300,400,   1.5, 2.0,
                                                         appear in the crop                                               600         3.0
                        Cotton Leafworm                  and repeat at regular
                        Spodoptera spp.                  intervals throughout                                             500,600,   2.5, 3.0,
                        Leaf Perforator                  the season                                                       200        3.5
                        Bucculatix thurberiella
                        Spiny (Spotted) Bollworm
                        Earias spp.

                        Whitefly                         Spray when whitefly first appear                                 500,600,   2.5, 3.0,
                        Bemisia tabaci                   in the crop and repeat at regular                                700        3.5
                                                         intervals throughout the season.

                        Thrips spp.
                        Aphida                           Spray when these pests first                                     500, 600,  2.5, 3.0,
                        Aphis spp.                       appear in the crop and                                           700        3.5
                        Jassida                          repeat at regular intervals
                        Empoasca spp.                    throughout the season
                        Mites
                        Tetraaychus spp.

    DECIDUOUS           Panonychus ulmi                  Apply the first spray at 60-80%         20-60     1-3           400-1200      2-6
    TOP FRUIT                                            egg hatch and repeat at 2-3 week
                                                         intervals.

    TABLE 4. Continued...

                                                                                                                                              
                                                                                                           APPLICATION RATES
    CROP                PEST                             TIMING                                   High Volume                Low Volume
                                                                                             g a.i./hl   litres          g a.i./ha   litres
                                                                                                         AMITRAZ 20% EC              AMITRAZ
                                                                                                         1000 l water                20% EC/ha
                                                                                                                                              
                        Mites                            Spray at the first sign of infestation  40-60     2-3           800-1200      4-6
                        Tetranychus spp. including       and repeat at 2-3 week
                        T. urticae, T. cinnabarinus      intervals.
                        and T. pacificus

                        Aculus schlectendali             Spray at the first sign of              20-30     1.0-1.5       400-600       2.3
                        Epitrimerus pyri                 infestation and continue at
                                                         regular 2-3 week intervals.

                        Codling Moth                     Apply the first spray immediately
                        Cydia pomonella                  after adult emergence and repeat
                                                         at 2-3 week intervals for at
                                                         least 5 applications.                   50-70     2.5-3.5       1000-1400     5-7
                        Aphids
                        Myzus persicae                   Apply at the first sign of
                        Aphys pomi                       infestation and repeat at regular
                        Dysaphis pyri                    2-3 week intervals.                     50-70     2.5-3.5       1000-1400     5-7
                        Eriosoma lanigerum               Will give good suppression
                        Phorodon humuli                  of aphids in an intensive
                        Dysaphis plantaginea             spray programme against mites.

                        Apple Maggot
                        Rhagoletis pomonella             Used in a full season's
                        White Apple Leaf Hopper          programme against mites will
                        Typhlocyba pomaria               give useful suppression of              50-70     2.5-3.5       1000-1400     5-7
                        San Jose Scale                   these pests.
                        Quadraspidictus perniciosus
                        Plum Curculio
                        Conotrachelus nenuphar

    TABLE 4. Continued...

                                                                                                                                              
                                                                                                           APPLICATION RATES
    CROP                PEST                             TIMING                                   High Volume                Low Volume
                                                                                             g a.i./hl   litres          g a.i./ha   litres
                                                                                                         AMITRAZ 20% EC              AMITRAZ
                                                                                                         1000 l water                20% EC/ha
                                                                                                                                              
    Pears only          Pear psylla                      Spray when attack first occurs and
                        Psylla pyricola                  repeat at regular intervals.  The       30-50     1.5-2.5       600-1000      3-5
                                                         higher rate is required to give
                                                         consistently good control of
                                                         over-wintering adults.

    Apples Only         Leaf miners
                        Leucoptera scitella              Apply the first spray at petal fall
                        Phyllonorycter blancardella      and repeat at 2-3 week intervals        40-50      2-2.5        800-1000      4-5
                                                         with a minimum of 4 applications

    CITRUS              Mites
                        Panonychus citri                 Apply first spray at 60-80% egg         20-50       1-3         400-1200      2-6
                                                         hatch and repeat at 2-3 week
                                                         intervals.
                        Tetranychus spp.                 Spray at first sign of infestation      40-60       2-3         800-1200      4-6
                                                         and repeat at 2-3 week intervals.
                        Phyllocoptruta oleivora          Spray at first sign of infestation      20-30      1-1.5        400-600       2-3
                                                         and continue at regular 2-3 week
                                                         intervals.
                        Scale Insects
                        Ceroplastea spp.                 Apply the first spray during the        50-60      2.5-3       1000-1200      5-6
                        Saissetia spp.                   crawler (larval) stage and repeat
                                                         at regular intervals.

    ORNAMENTALS
    Carnations,         Mites
    Chrysanthemums,     Panonychus ulmi                  Apply the first spray at 60-80%         30-50     1.5-2.5       600-1000      3-5
    Roses, Pot plants                                    egg hatch with repeat sprays at
    and other annuals                                    2-3 week intervals.
    and perennials

    TABLE 4. Continued...

                                                                                                                                              
                                                                                                           APPLICATION RATES
    CROP                PEST                             TIMING                                   High Volume                Low Volume
                                                                                             g a.i./hl   litres          g a.i./ha   litres
                                                                                                         AMITRAZ 20% EC              AMITRAZ
                                                                                                         1000 l water                20% EC/ha
                                                                                                                                              
    VEGETABLES          Tetranychus urticae              Spray at the first sign of infestation)
    SOFT FRUIT          Tetranychus pacificus            regular intervals                     )
                        and other Tetranychus                                                  )
                        species                                                                )
                        Acalitus essigi                                                        )
                        Aphids                           Under cold conditions                 ) 46-60        2-3        800-1200     4-6
                        Aphids gossypii                  and on some crops under glass,        )
                        Aulocorthum spp.                 the high rate may be necessary        )
                        Macrosiphum spp.                 to achieve consistently good          )
                                                         control
                                                                                                                                              
    

        TABLE 5.  Use of Amitraz on Crops.  Registrations (at August 1980) and Periods
    Between Last Application and Harvest

                                                                                  

    Country             Withholding      Crop1
                          Period
                                                                                  

    Argentina           4 weeks          apples
    Australia           4 weeks          pome fruit and stone fruit
    Belgium             4 weeks          apples, pears
    Bulgaria            not available    apples
    Chile               2 weeks          fruit, vegetables
    Cyprus              2 weeks          apples, peaches, citrus, cucurbits
    Czechoslovakia      1 week           cucumbers
                        4 weeks          apples, pears green beans, peppers, hops
    Denmark             2 weeks          apples, pears
    East Germany        4 days           cucumbers, tomatoes
                        4 weeks          apples, pears
    Ecuador             2 weeks          cotton, stone fruit, citrus, 
                                         strawberries, tomatoes, cucumbers
    El Salvador         not available    cotton
    France              30 days          fruit trees, pears
    Greece              1 week           apples, pears, citrus, vegetables
    Guatemala           not available    cotton
    Hungary             10 days          apples, plums, wild strawberries,
                                         vines, sugarbeet, soybeans
    Italy               2 weeks          citrus, vegetables, vines,
                                         stone fruit
                        4 weeks          apples, pears
    Japan               2 weeks          apples, pears, citrus
    Jordan              not available    top fruit
    Morocco             4 weeks          cotton, top fruit, vegetables
    Netherlands         4 weeks          apples, pears
    New Zealand         2 weeks          pome fruit and stone fruit
    Nicaragua           not available    cotton
    Pakistan            not available    cotton
    Peru                not available    cotton
    Portugal            4 weeks          apples, pears
    Romania             not available    top fruit
    South Africa        2 weeks          apples
                        4 weeks          cotton
    South Korea         not available    apples, pears, citrus
    Spain               1 week           fruit, maize
    Switzerland         3 weeks          apples, pears3
    Taiwan              not available    apples, pears, citrus
    Turkey              not available    apples, pears, citrus, cotton
    UK                  2 weeks          apples, pears
                        7 weeks2         hops
    USA                 4 weeks          pears
                                                                                  

    1 Use on ornamentals not included.
    2 Shorter withholding period under review - likely to be 4 weeks.
    3 Based on informal information, subject to written confirmation
    


        TABLE 6. Use Patterns on Animals

                                                                                                   

    Animal    Pests          Timing                                       Applications
                                                                                                   

    Cattle    ticks          A second application 10-14                   As a spray containing
              mange mites    days later may be necessary                  0.025% a.i.
              lice           for full control of mange and lice.

    Pigs      mange mites    Two applications, at low concentration       As a spray.
              lice           10-14 days after the first                   High concentration
                             will provide control.  Alternatively         0.1%
                             a single application at high concentration   Low concentration
                             may be recommended.                          0.05% a.i.

    Sheep     ticks                                                       As a dip at 0.05% a.i.
              mange mites                                                 Replenishments should be
              lice                                                        made with 0.075% amitraz
              keds

    Goats     ticks          A second application 0-14                    As a spray containing
              mange mites    days after the first my                      0.05% a.i.
              lice           be necessary for full control
                             of mange and lice.
                                                                                                   
    


        TABLE 7.  Use of Amitraz on Animals.  Registrations (at August 1980) and Periods Between Last
    Application and Slaughter

                                                                                          

    Country         Formulation1       Use/Animals                   Withholding Period
                                                                                          
    Argentina       12.5% e.c.         Dip for sheep                 None
    Australia       50% d.p.           Spray for cattle              None
                    50% d.p.           Dip for cattle                None
    Brazil          12.5% e.c.         Spray for cattle and          Meat 14 days2
                                       sheep                         Milk 1 day
    Colombia        12.5% e.c.         Dip for cattle                Meat 14 days2
                    12.5% e.c.         Spray for cattle              Milk 1 day
    Costa Rica      12.5% e.c.         Spray for cattle              None
    Cyprus          12.5% e.c.         Spray for cattle, sheep,
                                       goats and pigs                None
    Denmark         12.5% e.c.         Spray for pigs and            Meat 6 days
                                       cattle                        Milk 1 day
    Jordan          12.5% e.c.         Spray for sheep and goats     None
    Netherlands     12.5% e.c.         Dip for pigs and sheep        Pigs None
                                                                     Sheep 4 weeks
    Nicaragua       12.5% e.c.         Spray for cattle              None
    Rhodesia        12.5% e.c.         Spray for cattle              None
                    12.5% e.c.         Dip for cattle                None
    South Africa    12.5% e.c.         Spray for cattle              None
                    25% d.p.           Spray for cattle              None
                    25% d.p.           Dip for cattle                None
    Spain           12.5% e.c.         Spray for cattle, sheep,
                                       goats and pigs                None
    Sweden          12.5% e.c.         Spray or dip for cattle,      Sheep 7 days
                                       sheep and pigs                Pigs and cattle 1 day
    United Kingdom  12.5% e.c.         Spray for pigs and            Meat 1 day
                                       cattle                        Milk None
                    12.5% e.c.         Dip for sheep                 Meat 7 days
                                                                     Milk None
    Venezuela       12.5% e.c.         Spray for cattle              Meat 14 days2
                                                                     Milk 1 day
    Yugoslavia      12.5% e.c.         Cattle                        None
                                                                                          

    1 Emulsifiable concentrate is denoted by "e.c." and dispersible powder by "d.p.".
    2 These withholding periods were agreed upon early in the development programme
    before most residue work had been carried out.
    
    TABLE 8.  Species Of Skin Parasites Controlled By Amitraz

    (i) Ticks

    Boophilus microplus
    B. decoloratus
    Rhipicephalus evertsi
    Amblyomma hebraeum
    A. cayennense
    Hyalomma spp.
    Ixodes ricinus
    I. persulcatus
    I. holocyclus
    Haemaphysalis bispinosa
    H. longicornis

    ii) Mites

    Psoroptes spp.
    Sarcoptes scabiei
    Dermanyssus gallinae
    Demodex canis
    Psorergates spp.
    Chorioptes bovis

    iii) Lice

    Linognathus vituli
    L. ovillus
    Damalinia bovis
    D. ovis
    Haematopinus eurvsternus
    Solenopotes capillatus
    Haematopinus suis

    iv) Keds

    Melophagus ovinus


    RESIDUES RESULTING FROM SUPERVISED TRIALS

    The metabolite (II) (see figure 1) closely resembles amitraz in its
    toxicological effects and may be solely responsible for the signs seen
    when amitraz is ingested (see Toxicity of impurities, degradation
    products and metabolites, Table 3).  Effort was therefore concentrated
    on the measurement of the combined residues of amitraz and (II) in
    most countries (see Table 1 for structures).

    In the USA however, most of the trials have measured total residues as
    '2,4-xylidine moiety (IV).  For details of the analysis methods for
    both animal and vegetables products see "METHODS OF RESIDUE ANALYSIS".

    Residues in crops

    a. Apples and pears

    Residues have been determined on apples and pears from many countries
    representing a wide variety of climatic conditions.  Most trials have
    demonstrated that the total residue (amitraz plus (II), expressed as
    (II)) will not exceed 0.5 mg/kg, given an interval of 14 days between
    application and harvest, following use of amitraz at the recommended
    level, although the trials on pears in Italy gave somewhat higher
    residues.  See Table 9. for a summary of the trials and the results.
    Total residues determined in the USA, measured as mg/kg of
    '2,4-xylidine', indicate a similar decay pattern.  For details and
    results of the trials in the USA, see Tables 6/10/11.

    b. Stone fruits

    A summary of residue trials and results on stone fruits is given in
    Table 7.

    Peaches

    Residues of amitraz and its metabolites (II) and (III) have been
    measured on peaches grown in France.  The results obtained are very
    similar to those obtained for apples and pears.

    It is concluded that the total residue (amitraz plus (II)) will not
    exceed 0.5 mg/kg, given an interval of 14 days between application and
    harvest.

    Cherries

    Combined residues of amitraz and its metabolite (II) were measured on
    cherries in Denmark.  Residues ranged from 0.09 to 0.33 mg/kg, and
    seem unlikely to exceed 0.5 mg/kg given an interval of 28 days from a
    single application at recommended rates to harvest of crop.

    c. Oranges

    Total residues on treated oranges, grown in two areas of the USA, were
    measured.  Initial deposits on the fruit fell with half lives of about
    3 weeks to leave residues of around 0.5 mg/kg (expressed as amitraz)
    after 14 days.  Fruit harvested after 20 weeks contained a maximum
    residue of 0.060 mg/kg equally distributed between peel and fruit (see
    Table 13).




        TABLE 9.  Supervised Residue Trials on Pome Fruits in Various Countries

                                                                                                                                               
    Crop/Country   No. of
                   trials         Applications        Residues amitraz plus N-2,4-dimethylphenyl-N'-ethyl
                                                      formamidine expressed as the latter (mg/kg) at intervals              References
                                                                    (days) after application
                             No.  Rate per hectare
                                   kg      litres      0      7      14     21     28     35     42     49     56     63
                                                                                                                                               
    APPLES

    United Kingdom   5       1     1.4      1125       0.39-  0.18-  0.18-  0.18-  0.16-  0.07-  0.07-                      Hughes and Somerville,
                                                       0.48   0.44   0.41   0.35   0.41   0.17   0.30                       1973a
                                                                                                                            Hughes, Jones and
                                                                                                                            Somerville, 1974

    Netherlands      2       2     0.54      600                                   0.06-         0.04-                      Somerville and
                                                                                   0.07          0.05                       Hughes, 1973d
                     1       1     0.72     1800                     0.20          0.17                                     Goodall and Somerville,
                                                                                                                            1974 b

    France           1       2     0.60      880       0.60   0.47   0.42   0.32   0.17                                     ) Somerville and
                     1       1     0.60     1000       0.20   0.32   0.38   0.28   0.03                                     ) Hughes, 1973f

    USA              1       3     1.0      4500       0.37,  0.21   0.14   0.17   0.14   0.19                              )
                                                       0.38                                                                 )
                     1       3     2.0      4500       0.51,  0.46   0.42   0.35   0.38   0.18                              ) Anon., 1973
                                                       0.54                                                                 )
                     1       1     1.0      4500                     0.07   0.05   0.06                                     )
                     1       1     2.0      4500                     0.01   0.12   0.11                                     )

    Denmark          1       1     0.9      2250                                   0.44          0.05                 0.04  ) Somerville and
                     1       1     0.9      2250)             0.85          0.11          0.17                 0.03         ) Goodall, 1974
                             +2    0.67     2250)                                                                           )

    Italy            1       2     0.04 in 100 l
                                   at 15 l per
                                   tree                                            0.45                 0.34          0.23  Goodall and 
                                                                                                                            Somerville, 1974a

    TABLE 9.  Continued...

                                                                                                                                               
    Crop/Country     No. of
                   trials         Applications        Residues amitraz plus N-2,4-dimethylphenyl-N'-ethyl
                                                      formamidine expressed as the latter (mg/kg) at intervals              References
                                                                    (days) after application
                             No.  Rate per hectare
                                   kg      litres      0      7      14     21     28     35     42     49     56     63
                                                                                                                                               

    Switzerland                    1       1          0.2%    0.54   0.44   0.28   0.25   Anon., 1977

    Fed. Rep. of     5       3     0.75     1500       0.38-  0.33-  0.29-  0.26-  0.16-                                    Richards, 1980b
    Germany                                            1.01   1.03   0.71   0.72   0.781


    PEARS

    UK               2       1     1.4      1125       0 36,  0.37,  0.12,  0.13,  0.07,  0.09                              Hughes, Jones and
                                                       0.46   0.38   0.27   0.17   0.15   0.09                              Somerville, 1074

    USA              1       1     1.32     2950       0.54   0.49   0.10                                                   ) Anon., 1973
                     1       1     2.64     2950       1.00   0.92   0.84                                                   )

    Italy            2       2     0.60     1000       1.80,         1.42          0.02         0.02,          0.01         )
                                                       1.90          0.84          0.56         0.18           0.11         ) Goodall and 
                     1       2     (50 g in 100 l.     1.54          0.94          0.53         0.43           0.26         ) Somerville, 1974a
                                   to run off)                                                                              )

    Japan            1       2     1.5      6000       0.30          0.15   0.19   0.06                                     Summary only
                                                       0.21

    Switzerland      1       1     0.2%                0.5    0.56   0.39   0.24                                            Anon., 1977
                                                          0.63

    Fed. Rep. of
    Germany          1       3     0.75     1500                     0.10   0.10   0.10                                     Richards, 1980b
                                                                                                                                               

    1 The highest figures were all obtained from one anomalous trial.  In the others residue levels from 14 days were not above 0.50 mg/kg.
    

        TABLE 10.  Supervised Residue Trials on Apples in USA

    Residues expressed as amitraz calculated from total '2,4-xylidine' moiety

                                                                                   
    Location           Application                   Residues in mg/kg at
                                              intervals (days) after application
    State             Rate per hectare   0,1,2     7,8       14,15     21,23     28
    in USA      No.    kg     litres
                                                                                   
    Michigan     9     1.3     3590                1.03      1.16
                                                   1.79      1.15

    Michigan     1     1.2     3590      0.72      0.57      0.28
                                         0.86      0.91      0.38
                                         1.34      1.11      0.74

                       1.3     3590      0.64      0.66      0.35

    Michigan     6     1.2     3590      2.33      1.68      1.79
                                                   2.31      1.32

                                         2.33      3.03      2.13
                                                   2.89      1.74

                                         2.45      1.66      1.75
                                                   2.66      2.19

                       1.3     3590      2.15      1.12      1.48
                                                   0.98      1.87

    Michigan     3     1.4     1870      1.49      1.37      1.02
                                         1.66      1.28      0.88

    Michigan     1     1.4     1870      0.58      0.36      0.46
                                                   0.67      0.25

                       1.39     374      1.54      0.90      0.53
                                                   0.90      0.78

    Michigan     1     0.56     140                                    0.11
                                                                       0.14

    New York     3     1.22    3272      0.43      0.28      0.32
                                         0.40      0.50      0.44

    New York     1     1.39    3740      0.32      0.28      0.20
                                         0.52      0.35      0.24

    North        3     1.07    2870      0.45      0.76      0.25
    Carolina                             0.72      0.59      0.42

    TABLE 10.  Continued...

    Residues expressed as amitraz calculated from total '2,4-xylidine' moiety

                                                                                   
    Location           Application                   Residues in mg/kg at
                                              intervals (days) after application
    State             Rate per hectare   0,1,2     7,8       14,15     21,23     28
    in USA      No.    kg     litres
                                                                                   

    Oregon       1     1.86     467      0.99      1.68      0.87
                                         1.46      0.38      0.81

    Washington   1     1.86    3740      0.96      0.89      1.02
                                                   0.51      1.00

    California   2     0.70     467      1.00      0.63      0.46
                                         0.63      1.15      0.54

                       0.70    3740      1.71      1.79      0.80
                                         1.24      1.44      1.13

    Wisconsin    2     1.39    3740      0.79      0.24      0.24
                                         0.54      0.30      0.27
                                                                                   

    Anon., 1975
    
        TABLE 11.  Supervised Trials on Pears in USA

    Residues expressed as amitraz calculated from total '2,4-xylidine' moiety

                                                                                       
    Location             Applications            Residues in mg/kg at
                                          intervals (days) after application
    (State
    in USA)      No.   Rate per hectare
                        kg      litres    0,1       3         7,8       14,15     16,17
                                                                                       
    California   3     1.85      1870     0.78                0.66      0.69
                                          0.50                0.69      0.54

    California   3     1.86       467     0.52                0.30      0.32
                                          0.45                0.34      0.42

    Michigan     3     0.88      2945     0.30
                                          0.47

                       1.46      2945     1.18                0.62      0.49
                                          0.96                0.42      0.56

    Michigan     1     0.56      1122     0.31      0.43      0.32      0.31
                                          0.30      0.41      0.38

    Michigan     1     1.32      2945     1.20                0.81      0.66
                                          1.36                0.86      0.25
                                          1.67                1.04      0.27
                                          1.26                0.75      0.31

    Michigan     3     1.46      2945     0.89                1.17
                                          1.17                1.36
                                          1.19                0.94
                                          1.22                1.03
                                          1.20                1.03
                                          1.36                1.40

    Michigan     2     1.39      1402     0.82                0.65      0.34

                       1.39       280     1.16                1.09      0.87
                                                                        0.47

    New York     5     1.85      3740     1.69                1.07      0.97
                                                              0.87      0.68

    New York     6     1.63      3272     1.74                1.37      1.22
                                          2.38                2.38      1.37

    Oregon       5     1.87       467     0.92                0.78      0.95
                                          1.28                0.75      0.43

    TABLE 11.  Continued...

    Residues expressed as amitraz calculated from total '2,4-xylidine' moiety

                                                                                       
    Location             Applications            Residues in mg/kg at
                                          intervals (days) after application
    (State
    in USA)      No.   Rate per hectare
                        kg      litres    0,1       3         7,8       14,15     16,17
                                                                                       

    Oregon       6     2.79      5610     1.80                1.48      1.36
                                          2.75                1.22      1.07

    Washington   5     1.86      1309     1.19      1.02      0.96      0.51
                                                              0.28
                                          0.34      1.10      0.75      0.30
                                                              0.40

    Washington   5     1.86      3740     1.12                0.55      0.85
                                          0.99                0.65      0.72

    Washington   6     8.198 g/l          0.12                          0.12
                       undiluted          0.14                          0.12
                                                                                       

    Anon., 1975
    



        TABLE 12.  Supervised Residue Trials on Stone Fruits

    Residues of amitraz plus N-2,4-dimethylphenyl-N'-methylformamidine expressed as the latter

                                                                                                                                    

                                                 Applications           Residues in mg/kg intervals (days)
                                No.            Rate per hectare                  after application                  References
                   Country      of       No.     kg    litres       0     7     14    21    28    35    49    63
    Crop                      Trials
                                                                                                                                    

    Cherries       Denmark      2        1      0.675   3,375                  0.28        0.09                     Humphrey and
                                                                                                                    Somerville,1976

    Sour Cherries  Denmark      3        1      0.40    1,000                                     0.33  0.09  0.17  Hayto, 1978d

    Plums          UK           2        1         1.26 g/l                    0.041       0.241                    Hayto, 1977c

    Peaches        France       4        1      0.60    1,000      0.57- 0.32- 0.24- 0.15- 0.04,                    )Somerville and
                                                                   1.03  1.03  0.30  0.24  0.06                     )Hughes, 1973b,c

                                1        1      0.32    1,900      0.72  0.21  0.10  0.21  0.06                     Somerville and
                                                                                                                    Hughes, 1973c
                                                                                                                                    

    1 These two results were obtained on different varieties of plum at different locations.
    
    d. Cotton

    Residues of amitraz and its metabolite (II) have been measured in
    cotton from several different territories.  Most of the determinations
    have been made on cotton seed following a normal spray programme.  In
    the case of South Africa, the seed was fractionated into cake and oil,
    which were analysed separately; much shorter last spray to harvest
    intervals were used than in a normal spray programme.  The combined
    residues (expressed as (II)) never exceeded 0.4 mg/kg.  A summary of
    these cotton residue trials can be found in Table 14.

    Total '2,4-xylidine' residues (expressed as amitraz) measured in the
    USA indicated that after 14 days residues were below 0.5 mg/kg except
    in one instance.  See Table 15.

    e. Hops and beer

    Treated samples of hops, both green and dried, have been analysed for
    residues of amitraz and its metabolite (II).  The combined residues, 7
    weeks after the final application, were 0.03 and 0.11 mg/kg (expressed
    as (II)) for the green and dried hops respectively.  No detectable
    residues were found in beer made with treated hops.

    f. Cucumbers

    Residues of amitraz and (II) have been measured in cucumbers treated
    in the UK, Netherlands and South Africa.  In all cases the combined
    residues after three days never exceeded 0.3 mg/kg in the whole fruit
    or the skin.

    g. Olives

    Residues of amitraz and its metabolite (II) have been measured in
    olive oil and pressed olives treated in Italy.  The results are in
    Table 16.

    h. Eggplants

    Eggplants were treated with amitraz in Italy.  Combined residues were
    below 0.3 mg/kg after 4 days.

    i. Onions

    In a similar study, amitraz was applied to onions.  Combined residues
    after 28 days were an average of 0.06 mg/kg.

    Table 16 summarises the residue data on vegetables, hops and beer.



        TABLE 14.  Supervised Residue Trials with Cotton in Various Countries: Residues in cottonseed, seedcake and oil

    Residues of amitraz plus N-2,4-dimethylphenyl-N'-methylformamidine expressed as the latter

                                                                                                                           
                                          No.
                 Rate of Application      of       Residues in mg/kg at intervals (days) after application   References
    Country            kg/ha          Treatments     5      19     21    28    37    41    77    80
                                                                                                                           

    Turkey             0.8                3                                                     <0.01         ( Hamilton,
                       1.0                3                                                     <0.01         ( 1977a

                0.8 in 4001 followed      2                                               <0.01
                   by 0.6 in 6001                                                      (in seed oil)          Hayto, 1978f

    Guatemala          0.29               21                            <0.01,0.02                            )
                       0.57               21                            <0.01,0.01                            )
                                                                                                              )
    Colombia           0.5)                                                   )                               ) Hayto, 1978a,
                       0.7)-in 4001       7                                   )<0.01                          )
                       1.0)                                                   )                               )

    S. Africa          0.4                1          0.05   0.05         0.05 (seedcake)                      )
                                                     0.03   0.18         0.04 (oil)                           )
                                                                                                              )
                       0.6                1          0.13   0.06         0.11 (seedcake)                      ) Hayto, 1978c
                                                     0.22   0.09         0.04 (oil)                           )
                                                                                                              )
                       0.8                1          0.28   0.21         0.29 (seedcake)                      )
                                                     0.22   0.34         0.29 (oil)                           )

    Mexico             0.2 kg/l           6                        0.02 (seed cotton)
                                                                   0.05 (seed from whole bolls)               Hayto, 1978e
                                                                                                                           

    1 The first application was ULV; the second conventional application.  Samples tested were cottonseed except where
    treated otherwise.


    TABLE 15.  Residues on Cottonseed in U.S. trials

    Residues expressed as amitraz calculated from total '2,4-xylidine' moiety

                                                                                                          
    State of                                            No. of              Residues in mg/kg at
    U.S.A.         Rate of Application per hectare    Treatments     intervals (days) after application
                                                                    0    6,7    9    14    18    48    85
                                                                                                          
    Texas                 0.28 kg in 37.4 l                9       1.04  0.80        0.68
                          0.14 kg in 37.4 l                9       0.16  0.18        0.21

    S. Carolina           0.28 kg in 46.7 l               16       0.16  0.12        0.13

    Alabama               0.56 kg in 121.6 l              11             0.41

    Mississippi           0.14 kg in 46.7 l               10                                    0.20
                          0.14 kg in 28.0 l                4                               0.12
                          0.28 kg in 56.1 l               12                   0.27  0.28

    Alabama               0.56 kg in 46.7 l                6                                          0.06
                          0.28 kg in 46.7 l                6                                          0.07
                                                                                                          

    Anon., 1978


    TABLE 16.  Supervised Residue Trials on Vegetables, Hops and Olives (Oil and Cake)

    Combined residues of amitraz and N-2,4-dimethylphenyl-N'-methylformamidine expressed as the latter

                                                                                                                           
    Crop           Country                  Applications        Residues (mg/kg) at intervals (days)
                                No.       Rate per hectare                 after application               References
                                           kg      litres         0,1    3    4,5    6,7   14    28
                                                                                                                           

    Cucumber         UK          1            0.33 g/l                  0.09                               ) Hamilton 1978
                                 2            0.33 g/l                        0.13   0.09                  )

    Cucumber       S. Africa     1      60 g in 100 l drench      0.30  0.30  0.10                         ) Hayto, 1979
                                                                  0.37                                     )

    Cucumber       Netherlands   1         2.8     7,000                0.02,<0.01                         )
                                                                        0.03, 0.07                         )
                                                                                                           )
                                 1         2.4     6,000                0.01                               ) Somerville and
                                                                        0.13                               ) Hughes, 1973a,
    Eggplant                     1         0.51    1,000          0.17        0.27   0.18        0.12      )
                                                                                                           ) Hayto, 1978b
                                                                                                           )
    Onion bulbs                  1         0.5                                                   0.06      )
                                                                                                                           


    TABLE 16.  Continued...

                                                                                                                           
    Crop         Country       No.                Applications    Residues (mg/kg) at intervals (days)
                               of       No.     Rate of hectare              after application             References
                             Trials              kg     litres       50       54       90       139
                                                                                                                           

    Hops and
    beer           UK

    Green Hops     UK          1         1      0.72                0.03                                   )
                                                                                                           )
    Dried Hops     UK          1         2      0.72                0.11                                   ) Hamilton, 1977b
                                                                                                           )
    Beer           UK          1         2      0.72 (on hops)      1.68     <0.01                         )

    Olives        Italy        2         1         54 g/hl                                                 )
                                                                              1.68     1.36 (Pressed cake) )
                               2         1        108 g/hl                                                 ) Richards, 1980a
                                                                             <0.01    <0.01 (Purified oil) )
                                                                              0.80     1.70 (Pressed cake) )
                                                                                                                           
    

    Residues in animals

    Cattle

    Trials have been carried out on cattle and calves in order to measure
    combined residues of amitraz and (II), total '2,4-xylidine', or (V)
    residues, in tissues after single or repeated applications of amitraz
    as a spray or dip.  Combined residues of amitraz and (II) and total
    '2,4-xylidine' residues after hydrolysis were generally comparable to
    control values 1 and 7 days after single spray applications.  As
    expected, some residues of (V) were apparent after hydrolysis of the
    tissues.  The results, however, were often complicated by
    naturally-occurring 4-amino-benzoic acid, which was not resolved from
    (V) by the original method of analysis and gave rise to apparent
    residues in untreated tissues.  The maximum corrected residue of (V)
    after a single-spray application was 0.50 mg/kg in the liver.

    Long-term trials involving spray or dip programmes indicated no large
    accumulation of residues.  Maximum residues of amitraz plus (II) were
    0.13 mg/kg in the kidney 1 day after a 14-month spray programme. 
    Liver tissues from the same trial gave rise to corrected maximum
    residues of 0.89 mg/kg of (V).

    Milk samples and butter fat have been analysed for combined residues
    of amitraz plus (II), for residues of (V), and also for total
    '2,4-xylidine' residues.  No significant residue were found in milk.
    Maximum levels of '2,4-xylidine' occurred in butter fat 6 hours after
    treatment (0.15 mg/kg amitraz), however milk collected 2 days after
    treatment showed no significant residues as did factory butter
    produced locally.

    Sheep

    In sheep, total residues of '2,4-xylidine' one day after a single dip
    were below 0.1 mg/kg in muscle, and below 0.5 mg/kg in kidney and fat,
    except in the case of back fat in the first trial.  Residues of the
    terminal metabolite (V) were only significant in liver and kidney
    (corrected maximum 0.65 mg/kg).  Milk samples from treated sheep gave
    no significant residues of amitraz plus (II) after 1 or 2 days.

    Pigs

    Residues of amitraz plus (II), and total residues of '2,4-xylidine',
    were comparable to control values in pigs sprayed once and twice
    respectively.  Analysis of pigskin indicated combined residues of
    amitraz plus (II) of 0.04 mg/kg and 0.01 mg/kg at 1 and 3 days after a
    single spray.

    Tissues from the double spray trial gave rise to residues of (V).
    However, an apparent residue of over 1 mg/kg in the liver was
    confirmed at 0.40 mg/kg by combined gas chromatography-mass
    spectroscopy.  Smaller residues were likewise found in other tissues.

    A summary of all residue results from animal trials can be found in
    Table 17.

    FATE OF RESIDUES

    In plants

    Experiments using 14C-amitraz demonstrated that, under certain
    conditions at least residues of (II) and (III) could occur on and in
    fruit, e.g. apples (Somerville and Nicholson, 1972).

    The radiotracer experiments also demonstrated that 14C-amitraz,
    applied to leaves, was not transported in any measurable quantity to
    other parts of the plant, whereas when 14C-amitraz was applied to the
    soil, radioactivity could be taken up into the aerial portions of
    plants (Somerville and Spiers, 1972; Lewis, 1970b).

    The metabolic pathway is summarised in figure 1.

    In animals

    The metabolism of amitraz in animals is covered fully in Biochemical
    Aspects.

    Studies with dogs, cats, rats, mice and bovines all yield the same
    picture, namely that amitraz does not persist in vivo, but is
    rapidly degraded, yielding conjugated 4-amino-3-methylbenzoic acid (V)
    which is excreted in the urine.  In dogs, evidence has been obtained
    indicating that the first step in the degradation is simple hydrolysis
    to yield N-(2,4-dimethylphenyl)-N'-methylformamidine (II) and
    2,4-dimethylformanilide (III).  This is consistent with the known
    properties of amitraz in acid medium.  Furthermore, in an experiment
    in which (II) was itself fed to dogs, identical excretory products to
    those yielded by amitraz were found.  In vitro studies have shown
    that both (II) and (III) are degraded rapidly in gastric juice to give
    2,4-xylidine (IV).

    Further evidence that (IV) is an intermediate in amitraz degradation
    in animals is provided by Lindstrom (1961) who showed that (IV) was
    rapidly converted to (V) in rats.

    It is also of interest to note that (V) is found in human urine
    following exposure to amitraz indicating that the same pathway of
    metabolism exists in humans.

    Once ingested, amitraz is rapidly converted to metabolite (II), which
    has similar toxicological effects to amitraz itself.  Since apple
    pomace and citrus pulp may be fed to cattle, analyses were made of
    plasma, tissues and milk from calves and cows dosed with (II).  No
    measurable residues of (II) or (V) were found in the milk of cows
    after 21 days continuous dosage (Dickinson and Shirley, 1975).  After
    a similar period the total residues of (II), (III), and (IV) in


        TABLE 17. Supervised Residue Trials on Animals in Various Countries

                                                                                                                                               
    Country      Animal/                                                      Residues at intervals (days) after application.
                Commodity                          Application                Amitraz plus N-2,4-dimethyl-N'-methyl-formamidine  References
                                                                              expressed as the latter (mg/kg) unless
                                                                              stated otherwise.
                                    Type         Number       Concentration         CONTROL       1         4        7/8
                                                                                                                                               

    UK           CATTLE             spray         once           0.025%

                 muscle    )                                                         <0.01      <0.01                0.01        )
                 liver     )                                                         <0.01       0.05               <0.01        )
                 kidney    )                                                                    <0.01                0.03        )
                 fat                                                                 <0.01      <0.01               <0.01        )
                                                                                                                                 )
                 muscle    )3                                                         0.051     <0.01                0.02        ) Jones and
                 liver     )                                                          0.061      0.12                0.02        ) Holland,
                 kidney    )                                                                     0.03                0.01        ) 1974
                 fat       )                                                          0.091      0.01                0.01        )

    UK           CATTLE             spray         once           0.025%

                 muscle    )                                                          0.02      <0.01                            )
                 liver     )                                                         <0.01      <0.01                            ) Holland,
                 kidney    )                                                          0.03       0.01                            ) Jones and
                 fat       )                                                         <0.01       0.03                            ) Jones, 1974

    Australia    CATTLE             spray      repeatedly at     0.025%
                                              7-day intervals
                 muscle (rump) )               followed by 3                         <0.01      <0.01      <0.01                 )
                 (shoulder)    )               sprays at 3-day                       <0.01    <0.01-0.02   <0.01                 )
                 liver         )               intervals                             <0.01       0.01      <0.01                 ) Hayto,
                 kidney        )                                                     <0.01     0.03-0.04    0.03                 ) 1977b
                 fat (back)    )                                                     <0.01      <0.01      <0.01                 )
                  (omental)    )                                                     <0.01      <0.01      <0.01

    TABLE 17. Continued...
                                                                                                                                              
    Country      Animal/                                                      Residues at intervals (days) after application.
                Commodity                          Application                                                                   References

                                    Type         Number       Concentration         CONTROL       1         4        7/8
                                                                                                                                              

    S. Africa    CATTLE                     spray weekly         0.05%
                                                  for 14
                 muscle    )3                                                        <0.011                          0.05        )
                 liver     )                                                         <0.01                           0.06        )
                 kidney    )                                                                     0.13                            )
                 fat       )                                                          0.01                           0.06        )
                                                                                                                                 )
                 muscle    )3                                                         0.051      0.02                0.03        ) Holland
                 liver     )                                                          0.061      0.04                0.03        ) and Jones,
                 kidney    )                                                                     0.11                0.12        ) 1974a
                 fat       )                                                          0.091      0.03                0.03        )

                 milk      )3                                                          0.02       0.02                0.01        ) Holland and
                                                                                                                                 ) Jones, 1974b

    S. Africa    CATTLE                    dipped weekly         0.008%
                                                  1-3 years

                 muscle    )3                                                         0.0051     0.008              <0.005       )
                 liver     )                                                          0.0051     0.04                0.01        ) Shirley,
                 kidney    )                                                          0.0051     0.06                0.01        ) 1977a
                 fat       )                                                          0.0051     0.02               <0.005       )

    TABLE 17.  Continued...

    Country      Animal/                                                      Residues at intervals (days) after application.
                Commodity                          Application                                                                   References

                                    Type         Number       Concentration         CONTROL       1         4        7/8
                                                                                                                                              


                                                                                     Day 0           Day 1          Day 2
                                                                                   am     pm       am     pm      am     pm
                                                                                 pre-treatment


    Australia    CATTLE                 dipped once              0.025%                                                          )
                                                                                                                                 )
                 tissues                                                                           <0.02        <0.02            )
                                                                                                                                 )
                                      dipped repeatedly          0.025%                                                          )
                                                                                                                                 )
                 milk             )                                                <0.012    <0.01 <0.01                         ) McDougall,
                 butterfat        )                                                <0.012     0.15  0.11  0.02   0.01    <0.01   ) Heath and
                 factory butter   )                                                             all samples 0.012                ) Black, 1979

    TABLE 17.  Continued...

    Country      Animal/                                                      Residues at intervals (days) after application.
                Commodity                          Application                                                                   References

                                    Type         Number       Concentration     CONTROL    1       3        5         7
                                                                                                                                              

    UK          SHEEP                  dipped once                0.05%

                muscle     )                                                   0.011    0.08                       0.07        )
                liver      )                                                   0.011    0.24                       0.11        )
                kidney     )                                                   0.021    0.40                       0.13        ) Shirley,
                fat (back) )                                                  <0.0051   0.62                       0.34        ) 1977b
                 (omental) )                                                  <0.0051   0.14                       0.08        )

    UK          SHEEP                  dipped once                0.05%

                muscle (shoulder)                                              0.012    0.03    0.02     0.01      0.01        )
                       (hind leg)                                              0.012    0.03    0.01     0.01      0.01        )
                liver                                                          0.012    0.13             0.04      0.03        ) Needham and
                kidney                                                         0.012    0.27             0.09      0.07        ) Campbell,
                fat (back)                                                     0.012    0.26    0.27     0.25      0.12        ) 1980
                 (omental)                                                     0.012    0.10    0.08     0.10      0.09        )

    TABLE 17.  Continued...

    Country     Animal/                                                       Residues at intervals (days) after application.
                Commodity                          Application                                                                   References

                                    Type         Number       Concentration     CONTROL    1       2        3         7
                                                                                                                                              

    UK            SHEEP                 dipped once               0.05%

                  milk                                                           <0.01    0.02    0.01    <0.01     <0.01        Shirley, 1978

    UK            PIGS                 sprayed once               0.1%                                 2 and 7 days
                                               twice at
                  muscle                       7-day                           <0.01-0.04               <0.01-0.02               )
                  liver                        intervals                       <0.01-0.05               <0.01-0.04               )
                  kidney                                                       <0.01-0.02               <0.01-0.07               ) Shirley,
                  fat                                                          <0.01-0.02               <0.01-0.02               ) 1975a

    UK            PIGS                 sprayed once               0.1%

                  skin                                                          <0.01     0.04             0.01     <0.01        Hayto, 1977a

    UK            PIGS                 sprayed twice              0.1%
                                               at 8-day
                  muscle                       intervals                       <0.031    <0.03                                   )
                  liver                                                        <0.031    <0.03                                   )
                  kidney                                                       <0.031    <0.03                                   ) Dickinson and
                  fat                                                          <0.031    <0.03                                   ) Shirley, 1976
                                                                                                                                              


    1 Total residues measured as '2,4-xylidine' and expressed as N-2,4-dimethyl-N'-methyl-formamidine (mg/kg) 
    2 Total residues measured as '2,4,xylidine' and expressed as amitraz (mg/kg) 
    3 No untreated animals in trial, tissues bought locally.
        tissues and plasma of calves were found to be < 0.01 mg/kg and < 0.1
    mg/l respectively, although the livers and kidneys of calves receiving
    the highest dose of 40 mg/kg diet/day contained residues of 0.02 and
    0.05 mg/kg respectively (Campbell and Needham, 1979).

    METHODS OF RESIDUE ANALYSIS

    Methods have been developed to measure combined residues of amitraz,
    compound (II), total '2,4-xylidine' (IV) and metabolites (V) and
    (III).

    Combined residues of amitraz (calculated as (II) and (II) are measured
    as mg/kg (II).  Fruit for analysis is first subjected to treatment
    with acidic methanol to convert amitraz to (II).  Solid material is
    filtered off, the extract cleaned and analysed by GLC using a
    flame-ionisation detector.  Sensitivity is 0.01 mg/kg and recoveries
    varied between 70 and 100% for different fruits (Hughes, 1974b;
    Somerville and Richards, 1980).

    Analysis of animal tissues and milk differ from the above only in the
    initial preparation of the sample for extraction, and in the cleanup
    procedures, which were slightly modified from those used for fruit.
    The method is capable of estimating a total residue level of 0.02
    mg/kg in lean meat, liver, fat and milk samples; recoveries were over
    70% and background levels were less than O.02 mg/kg (II) (Hughes,
    1974a).

    Methods of assay of total '2,4-xylidine' residues were developed for
    analysis of animal tissues.  The methods involve hydrolysis of
    amitraz, and all its metabolites that contain the moiety, to
    '2,4-xylidine' which on conversion to its heptafluorobutyric
    derivative can be determined by gas-liquid chromatography with
    electron capture detection.  The limits of sensitivity are 0.01 mg/kg
    (II) equivalents (Nappier, Hornish and Lane, 1976).

    Similar methods have been used in the USA for analysis of fruit and
    cotton seed, and lower limits of detection have been established at
    0.01 mg/kg and 0.05 mg/kg respectively (Nappier and Hornish, 1975;
    Nappier and White, 1978).

    Compound (V), the main mammalian metabolite of amitraz, exists as a
    conjugated derivative in tissues.  Analysis of residues of (V)
    therefore involves acid hydrolysis followed by high pressure anion
    exchange chromatography.  The method has a recovery of 70-80% and a
    lower level of detection of 0.03 mg/kg.  Relatively high background
    levels were found in earlier work, probably due to naturally occurring
    p-aminobenzoic acid, which eluted with (V).  The more recent method
    resolves these difficulties (Dickinson and Shirley, 1976).

    Compound(III) is formed in the hydrolysis of amitraz and has been
    assayed by high pressure liquid chromatography following extraction of
    fruit in the usual way.  The sensitivity of the method in 0.01 mg/kg
    and the recovery is 89%. (Jones, 1973 f).

    NATIONAL RESIDUE LIMITS

    The following national Maximum Residue Limits (MRLs) were reported to
    the Meeting.
                                                                     

    Country        Withholding    Crop                           MRL1
                   Period                                        mg/kg
                                                                     

    Australia      4 weeks        pome fruit and                 0.052
                                  stone fruit
    Belgium        4 weeks        apples, pears                  0.4
    East Germany   4 days         cucumbers, tomatoes            0.2
                   4 weeks        apples, pears                  0.2
    France         30 days        fruit trees, pears             0.15
    Hungary        10 days        apples, plums, strawberries,
                                  vines, sugarbeet, soybeans     0.052
    Italy          4 weeks        apples, pears                  0.4
                   2 weeks        citrus, vegetables,
                                  vines, stone fruit             0.4
    Netherlands    4 weeks        apples, pears                  0.4
    New Zealand    2 weeks        pome fruit and stone fruit     0.5
    Switzerland4   3 weeks        apples, pears                  0.3
    USA            4 weeks        pears                          3.03
    Fed. Rep. of                  apples, pome fruit             0.4
    Germany
                                                                     

    1 Combined residues of amitraz and formamidine (II), expressed as
    II, unless otherwise indicated.
    2 Amitraz only.
    3 Measured as total '2,4-xylidine' (IV), expressed as amitraz.
    4 Based on informal information, subject to written confirmation.


    EVALUATION

    COMMENT AND APPRAISAL

    Amitraz is an insecticide and acaricide effective against a wide
    variety of phytophagous mites and insects; its use on fruit and
    vegetables and on cotton is authorised in a large number of countries.
    It also has important veterinary uses, especially against the ticks
    and mites of cattle and sheep, including some otherwise resistant
    strains.  It is formulated as emulsifiable concentrates for both crop
    protection and animal use, and as wettable powders for animal use.

    Amitraz is well absorbed from the gastro-intestinal tract and
    eliminated from most tissues within a few days.  The metabolic
    breakdown is similar for all species studied, resulting in the
    formation of 3-methyl-4-aminobenzoic acid (BTS 28369) and its
    conjugates.

    With amitraz a number of short and long-term toxicity studies have
    been carried out with mice, rats and dogs.  From these experiments
    dogs appeared to be the most sensitive species.  Furthermore,
    experiments with amitraz metabolites showed that on the basis of
    weight BTS 27271 is more toxic than the parent compound, however this
    difference in toxicity may be explained by the difference in molecular
    weight between these compounds.  Therefore the toxicity of amitraz can
    most probably be attributed to the formation of BTS 27271.

    For mice and rats a marginal no toxic effect level of 2.5 and 3 mg/kg
    bw/day may be estimated.  In dogs however the no effect level from the
    short and long-term studies was 0.25 mg/kg bw/day.  The most
    predominant effect particularly in dogs was CNS depression.  The
    metabolite BTS 27271 has a no effect level of 1 and 0.1 mg/kg bw/day
    for rats and dogs respectively.

    From reproduction and teratogenicity studies it was shown that amitraz
    influences mean litter size and viability of the young, although, in
    effective doses, toxicity on the dame was also apparent.  Therefore it
    can be concluded that amitraz is possibly embryotoxic in doses also
    toxic for the dama, but has no clear teratogenic activity.  However
    reported studies are incomplete with respect to the number of animals
    used (teratogenicity test) and the number of litters bred
    (multigeneration study).  Also no information was obtained about pre-
    implantation losses.  No information is available about the possible
    teratogenic potential of the metabolites.

    From mutagenicity tests with amitraz, BTS 27271, 27919, 28369, 33220
    and 24868 it was shown that only BTS 24868, 33220 and 27919 exhibit
    weak mutagenic activity in in vitro bacterial systems using
    Salmonella typhimurium (TA 100 strain).  Negative results were
    also obtained in the host-mediated and lethal tests with amitraz.

    With amitraz and BTS 24868 carcinogenicity experiments were carried
    out in mice and rats.  Amitraz was negative in the rat study, but from
    initial body weights it is concluded that the age of the animals at
    the start of the experiment was not within normal standards.  In the
    female mouse only 400 mg/kg bw caused an increased incidence of
    lymphoreticular tumours.  In female mice BTS 24868 increased the
    number of lung tumours.  In male rats (no female tested) also the
    number of lung tumours was found to be increased, together with
    bladder and liver tumours which were not seen in controls.  In these
    studies the number of animals used, dosing schedule and experimental
    period do not permit an evaluation of a possible carcinogenic action
    of BTS 24868.

    Human data are inadequate to be included in the evaluation for the
    acceptable daily intake.

    It should be remarked that a number of experiments and reports
    submitted do not meet acceptable standards.

    Experiments using 14C-amitraz show that under certain conditions the
    metabolites N-(2,4-dimethylphenyl)-N'-methylformamidine (II) and
    2,4-dimethyl-formanilide (III) may occur on or in fruit.  If 14C
    labelled amitraz is applied to soil some radioactivity may be taken up
    into the aerial parts of plants, but when it is applied to leaves
    there is no detectable movement to other parts.

    Extensive residue trials on apples and pears have taken place in the
    United Kingdom, Europe and other parts of the world, especially in the
    United States.  US registration authorities require that all
    components of the residue that give rise to '2,4-xylidine' on
    hydrolysis are included in the analyses, whereas elsewhere residue
    measurements are based on the determination of the parent compound
    plus N-(2,4-dimethylphenyl)-N'-methylformamidine (II), which is the
    most toxic metabolite, being more toxic to mammals than amitraz
    itself.  Further degradation gives compounds of lesser toxicological
    significance.

    It is suggested that results obtained by the two methods are broadly
    comparable when expressed on the same basis, although those based on
    hydrolysis to '2,4-xylidine' are sometimes rather higher.

    The terminal metabolite in animals, 4-amino-3-methyl benzoic acid (V),
    has been detected as a residue in animal tissues (especially in the
    liver), but it closely resembles the natural product 4-aminobenzoic
    acid (which can interfere with its determination).

    The residue analytical methods used in the USA, involving total
    '2,4-xylidine' determination, require a specially made
    distillation/extraction apparatus, and also involve the formation of a
    fluorinated derivative of the 'xylidine' before final determination by
    gas chromatography using electron capture detection.  These procedures
    probably require considerable skill on the part of the analyst.

    Convenient analytical methods, using gas chromatography with flame
    ionisation detection, are available for the determination of combined
    residues of amitraz and (II) in fruits, vegetables, animal tissues and
    milk, and these methods could be adapted for regulatory purposes.

     The meeting examined residues data from supervised trials reflecting
    established or proposed good agricultural practice on a number of
    crops and commodities.  From these data the meeting was able to
    estimate the maximum residue levels which were likely to occur when
    amitraz was used in practice and when reported intervals between last
    application and harvest were observed.

    Level of amitraz causing no toxicological effect

    Mouse:  2.5 mg/kg bw/day
    Rat:    3 mg/kg bw/day
    Dog:    0.25 mg/kg bw/day

    Estimate of temporary acceptable daily intake for man

    0 - 0.0005 mg/kg bw/day


    RECOMMENDATIONS OF RESIDUE LIMITS

    The meeting concludes that the maximum residue levels listed below are
    suitable for establishing maximum residue limits.  These levels refer
    to the sum of amitraz and N-(2,4-dimethylphenyl)-N'-methylformamidine
    (II), calculated as II.

                                                                      

    Crop                       FAO       MRL       Pre-harvest
                            Commodity  (mg/kg)       Interval
                              Group                   (days)
                                                                      

    Pome fruit                 10        0.5            14
    Peaches                    11        0.5            14
    Cherries                   11        0.5            28
    Cucumber                    7        0.5             3
    Oranges                     9        0.5             7
    Cottonseed                 20        0.5             7
    Cottonseed oil           class C     0.05
    Olive oil                class C     0.05    (Prepared from olives
                                                 (sprayed 60 days
                                                 (before harvest.

    Carcass meat
    of cattle                  25        0.05
    of pig                     25        0.05
    of sheep                   25        0.2

    Cattle meat by-products    27        0.2
    Pig meat by-products       27        0.2
    Sheep meat by-products     27        0.2
    Milk                       28        0.011/
                                                                      

    1/ Level at or about the limit of determination


    FURTHER WORK OR INFORMATION


    Required (by 1984)

    1. Long-term carcinogenicity study with 
    N-2,4-dimethylphenyl-N-methylformamidine.

    2. Long-term carcinogenicity study with amitraz in mice.

    3. Further information on the mutagenic activity of 2,4-xylidine,
    NN-bis(2,4-dimethylphenyl)formamidine and 2,4-dimethylformanilide.

    4. Additional residue data from supervised trials on whole olives.

    Desirable

    1. Information on the teratogenic activity of
    N-2,4-dimethylphenyl-N-methylformamidine.

    2. Information on species differences in toxicity.

    3. Further observations in humans.

    4. Additional residue data on citrus fruits.

    5. Further trials on hops, onions and eggplants.


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    Identification of major liver metabolite. Unpublished report no.
    F 73011; 1973b, from The Boots Company submitted to WHO.

    Jones, E.M. Metabolism of [14C]-BTS 27419 in rats. Unpublished report
    no. F 73010; 1973c, from the Boots Company submitted to WHO.

    Jones, E.M. Metabolism of [14C]-BST 27271 in dogs. Unpublished report
    no. F 73019; 1973d, from The Boots Company submitted to WHO.

    Jones, E.M. Metabolism of [14C]-BTS 27419 in cats. Unpublished report
    no. F 73018; 1973e, from The Boots Company alimitted to WHO.

    Jones, E.M. Residue analyses of BTS 27919 on French peach crops
    (Report no. 1). Boots Co. Ltd. report no. F 73015; 1973f,
    (Unpublished).

    Jones. E.M. and Holland, G.N. Analysis of amitraz and its metabolite
    BTS 28369 in treated Thurgarton calves. Boots Co. Ltd. report no.
    F 74020; 1974 (Unpublished).

    Kakuk, T.J. Amitraz. Further evaluation of 80-week mouse study.
    Unpublished report no. HGD 79002; 1979, from The Boots Company
    submitted to WHO.

    Lancaster. M.C. and Williams, G.A.H. Amitraz: Multigeneration feeding
    test in rats - Histopathology. Unpublished report no. TX 78064; 1978,
    from The Boots Company submitted to WHO.

    Lewis, D.K. RD 27.419. Metabolism and residue studies in the calf
    using (14C) and (3H)-labelled material. Unpublished report no.
    C 70029; 1970a, from The Boots Company submitted to WHO.

    Lewis, D.K. Amitraz - a preliminary study of the persistence,
    translocation, and metabolism in plants. Boots Co. Ltd. report no.
    FM 70158; 1970b, (Unpublished).

    Lewis, D.K. Fate of [14C]-triazid applied to rats as a single oral
    dose. Unpublished report no. C 71011; 1971a, from The Boots Company
    submitted to WHO.

    Lewis, D.K. Fate of [14CH]-BTS 27419 applied to rats as a single
    dermal dose. Unpublished report no. C 71019; 1971b, from The Boots
    Company submitted to WHO.

    Lewis. D.K. Fate of [14C]-BTS 27419 applied to dogs as a single oral
    dose. Unpublished report no. 71024; 1971c, from The Boots Company
    submitted to WHO.

    Lewis, L. Fate of [14C]-triazid (BTS 27419) in the calf. Unpublished
    report no. C 71026; 1971d, from The Boots Company submitted to WHO.

    Lindstrom, H.V. The metabolism of FD and CRED no. I. The fate of
    2,4-meta-xylidine in rats. J. Pharm. Exp. Therap. 132, 306-310.

    Martin, H., and Worthing, C.R. Pesticide Manual, 6th Edition, p. 15.
    Published by the British Crop Protection Council.

    McDougall, D.W., Heath, A.B., and Black. R.R. Residues of amitraz in
    the tissues, milk, and butter of cattle dipped in Taktic. Aust. J.
    Exp. Agric. Anim. Husb., 19: 663-665.

    Merryman, D.C. and Sutton, M.M. BTS 27419. Effects on the oestrus
    cycle of the rat. Unpublished report no. PN 72003; 1972, from The
    Boots Company submitted to WHO.

    Moore, W.K.S. Clinical observations during development. 1972,
    Unpublished report from The Boots Company submitted to WHO.

    Morgan, H.E. BTS 27271. Acute oral toxicity study in dogs. 
    Unpublished report no. TX 73004; 1973a, from The Boots Company
    submitted to WHO.

    Morgan, H.E, BTS 28037; Acute oral toxicity study in dogs. Unpublished
    report no. TX 73015; 1973b, from The Boots Company submitted to WHO.

    Morgan, H.E. BTS 27919: Acute oral toxicity study in dogs:
    Histopathology.  Unpublished report no. TX 74004; 1974a, from The
    Boots Company submitted to WHO.

    Morgan, H.E. BTS 28369: Acute oral toxicity study in dogs:
    Histopathology. Unpublished report no. TX 74006; 1974b, from The Boots
    Company submitted to WHO.

    Morgan, H.E., Ellicock, L.A., Parkinson, R. and Wood, R. Amitraz:
    comparison of oral and topical administration to pigs. Unpublished
    report no. TX 75025; 1975a, from The Boots Company submitted to WHO.

    Morgan, H.E., Patton, D.S.G. and Turnbull, G.J. BTS 27419: two year
    oral toxicity study in dogs. Unpublished report no. TX 73035; 1973,
    from The Boots Company submitted to WHO.

    Morgan, H.E. and Shepherd, G.M. BTS 28369: Acute oral toxicity study
    in dogs. Unpublished report no. TX 74001; 1974, from The Boots Company
    submitted to WHO.

    Morgan, H.E., Shepherd, G.M., and Turnbull, G.J. BTS 28369: 90-day
    oral toxicity study in dogs. Unpublished report no. TX 74037; 1974,
    from The Boots Company submitted to WHO.

    Morgan, H.E. and Turnbull, G.J. BTS 27919: Acute oral toxicity study
    in dogs. Unpublished report no. TX 73034; 1973, from The Boots Company
    submitted to WHO.

    Morgan, H.E., Turnbull, G.J. and Ellicook, L.A. Amitraz and BTS 27271:
    Effects of repeated daily dosing on acute responses in dogs.
    Unpublished report no. M 75026; 1975b, from The Boots Company
    submitted to WHO.

    Morgan, H.E. and Williams, G.A.H. BTS 27271: Acute oral toxicity study
    in dogs -Histopathology. Unpublished report no. TX 73030; 1973a, from
    The Boots Company submitted to WHO.

    Morgan, H.E. and Williams, G.A.H. BTS 28037: Acute oral toxicity study
    in dogs. Unpublished report no. TX 73038; 1973b, from The Boots
    Company submitted to WHO.

    Nappier, J.L. and Hornish, R.E. Total residue method for U-36, 059
    (amitraz) in apples, pears, and soils. Upjohn Co. report no.
    315-9760-32; 1975, (Unpublished).

    Nappier, J.L., Hornish, R.E. and Lane, R.E. Total residue method for
    U-36,059 (amitraz) in swine tissue. Upjohn Co. report no. 315-9760-70;
    1976, (Unpublished).

    Nappier, J.L. and White, M.C. Total residue method for U-36, 059
    (amitraz) in cotton seeds. Upjohn Co. report no. 315-78-9760-001;
    1978, (Unpublished).

    NCI, Final Report. Carcinogenicity of chemicals present in man's
    environment. Contract no. NIH-NCI-E-68-311. Reported by Bio-Research
    consultants, 1973, submitted to WHO by The Boots Company.

    Needham, D. and Campbell, J.K. Amitraz residues in the tissue of sheep
    1,3,5 and 7 days after dipping in 0.05% amitraz. Boots Co. Ltd. report
    no. AX 80016; 1980, (Unpublished).

    Nix, N. Stability data for Amitraz Technical (Paraformaldehyde Sachets
    Stabilised). Unpublished report dd. 11-12-1979; 1979, from The Boots
    Company submitted to WHO.

    Palmer, A.K. and James, P.A. Dominant lethal assay of amitraz in the
    female mouse. Unpublished report no. BTS 81/7758; 1977a, from
    Huntingdon Research Centre, submitted to WHO by The Boots Company.

    Palmer, A.K. and James, P.A. Dominant lethal assay of amitraz in the
    male mouse. Unpublished report no. BTS 80/7792; 1977b, from Huntingdon
    Research Centre, submitted to WHO by The Boots Company.

    Parkinson, R. The effects of BTS 27271, BTS 27419 and BTS 21103
    (chlordimeform) on the central actions of reserpine in the mouse and
    rat. Unpublished report no. P 74033; 1974a, from The Boots Company
    submitted to WHO.

    Parkinson, R. The effects of BTS 27271, BTS 27419 and BTS 21103
    chlordimeform) on the pressor response to tyramine in the pithed rat.
    Unpublished report no. P 74032; 1974b, from The Boots Company
    submitted to WHO.

    Parkinson, R. BTS 27271 - an attempt to produce and quantify the
    flushing response in the pig. Unpublished report no. P 75030; 1975,
    from The Boots Company submitted to WHO.

    Parkinson, R., Patton, D.S.G. and Yates, D.B.G. BTS 27419. Effects in
    conscious dogs of small intravenous doses. Unpublished report no.
    P 71535; 1971a, from The Boots Company submitted to WHO.

    Parkinson, R., Sim, M.F. and Yates, D. Effects of the acaricide BTS
    27419 and the related sulphur analogues BTS 30559 and BTS 30561 on the
    cardiovascular system of the cat, particularly the ear vascular bed.
    Unpublished report no. P 71576; 1971b, from The Boots Company
    submitted to WHO.

    Parkinson, R. and Yates, D.B. The effects of BTS 27419 on
    Trafuril-induced erythema on the guinea-pig. Unpublished report no.
    PM 71022; 1971, from The Boots Company submitted to WHO.

    Patton, D.S.G. RD 27271: Effects on u/v erythema in guinea pigs.
    Unpublished report no. PM 70100; 1970, from The Boots Company
    submitted to WHO.

    Patton, D.S.G. BTS 27419: Acute toxicity in baboons. Unpublished
    report no. TX 73002; 1973a, from The Boots Company submitted to WHO.

    Patton, D.S.G. BTS 27271: Effects in conscious dogs of small
    intravenous doses. Unpublished report no. TX 73017; 1973b, from The
    Boots Company submitted to WHO.

    Patton, D.S.G. and Sutton, M.M. Acute toxicity studies on BTS 27419 an
    acaricide. Unpublished report no. P 71544; 1971a, from The Boots
    Company submitted to WHO.

    Patton, D.S.G. and Williams, G.A.H. BTS 27419: 90-day toxicity study
    in dogs. Unpublished report no. P 71547; 1971b, from The Boots Company
    submitted to WHO.

    Petzold, G.L., Swenberg, J.A. and Bedell, M. Evaluation of amitraz
    (U-36,059) and its metabolites (U-40,481, U-36,893, U-54,915 A and
    U-54,914) in the DNA/Alkaline Flution assay. Unpublished report no.
    7268/77/7268/001; 1977, from The Boots Company submitted to WHO.

    Richards, M.E. Combined residues of amitraz and BTS 27271 in olives
    from Italy, 1978. Boots Co. Ltd. report nos. AX 79018 and 80029; 1979
    and 1980a, (Unpublished).

    Richards, M.E. Combined residues of amitraz and BTS 27271 in apples
    and pears from West Germany. Boots Co. Ltd. report no. AX 80001;
    1980b, (Unpublished).

    Shaw, J.W. BTS 27419 - acute intraperitoneal toxicity to rats.
    Unpublished report no. PM 71057; 1971, from The Boots Company
    submitted to WHO.

    Shaw, J.W. BTS 27419. Comparison of the acute oral and intraperitoneal
    toxicities to rats. Unpublished report no. TX 73006; 1973a, from The
    Boots Company submitted to WHO.

    Shaw, J.W. BTS 27419. Comparison of the acute oral toxicities to rats
    of BTS 27419 and BTS 27919. Unpublished report TX 73010; 1973b, from
    The Boots Company submitted to WHO.

    Shaw, J.W. BTS 27419 metabolite: 21-day chronic oral toxicity in rats
    of BTS 28369. Unpublished report no. TX 75058; 1975, from The Boots
    Company submitted to WHO.

    Shaw, J.W. and Williams, G.A.H. BTS 27419. 90-day chronic toxicity
    study in mice. Unpublished report no. TX 74016; 1974, from The Boots
    Company submitted to WHO.

    Shaw, J.W. and Williams, G.A.H. BTU 27419 metabolite: 90-day chronic
    oral toxicity in rats of BTS 27271. Unpublished report no. TX 75059;
    1975, from The Boots Company submitted to WHO.

    Shirley, D.B. Analysis of tissue from pigs treated with amitraz at
    Thurgarton Research Station. Boots Co. Ltd. report no. F 75015; 1975a,
    (Unpublished).

    Shirley, D.B. The analysis of BTS 28369 in the urine of amitraz
    production workers. Unpublished report no. F 75019; 1975b, from The
    Boots Company submitted to WHO.

    Shirley, D.B. The analysis of BTS 28369 in the urine of three amitraz
    production workers over a period of three weeks. Unpublished report
    no. F 75024; 1976.

    Shirley, D.B. Amitraz residues in cattle from Wiltonside, South
    Africa. Boots Co. Ltd. report no. F 77002; 1977a, (Unpublished).

    Shirley, D.B. Residue analyses of tissues from sheep treated with
    amitraz at Thurgarton Research Station, UK. Boots Co. Ltd. report no.
    F 77004, 1977b, (Unpublished).

    Shirley, D.B. Analysis of amitraz residues in sheep's milk. Boots Co.
    Ltd. report no. F 78013; 1978, (Unpublished).

    Sim, M.F. The diuretic action of the acaricides RD 27271 and RD 27419
    in mice. Unpublished report no. PM 70111; 1970, from The Boots Company
    submitted to WHO.

    Somerville, L. Fate of 14C-BTS 27419 in the lactating cow.
    Unpublished report no. C 72007; 1972, from The Boots Company submitted
    to WHO.

    Somerville, L. Fate of 14C-BTS 27419 administered to rats in repeated
    oral doses. Unpublished report no. AX 73011; 1973a, from The Boots
    Company submitted to WHO.

    Somerville, L. Fate of 14C-ring-labelled BTS 27419 in the calf.
    Unpublished report no. AX 73006; 1973b, from The Boots Company
    submitted to WHO.

    Somerville, L. Fate of 14C-BTS 27419 when administered to cats as a
    single oral dose. Unpublished report no. AX 73018; 1973c, from The
    Boots Company submitted to WHO.

    Somerville, L. and Goodall, E. Residue analyses of amitraz and its
    metabolite BTS 27271 on Danish apple crops. Boots Co. Ltd. report no.
    AX 74023; 1974, (Unpublished).

    Somerville, L. and Hamilton, D.Y. Studies on the accumulation and
    elimination of radio-labelled residues from dogs' eyes following oral
    administration of (14C)-BTS 27271. Unpublished report no. AX 74013;
    1974, from The Boots Company submitted to WHO.

    Somerville, L. and Hughes, K.W. Residue analyses of amitraz and its
    metabolite BTS 27271 on Dutch cucumber crops. Boots Co. Ltd. report
    no. AX 73008; 1973a, (Unpublished).

    Somerville, L. and Hughes, K.W. Residue analyses of amitraz and its
    metabolite BTS 27271 on French peach crops (Report no. 1). Boots Co.
    Ltd. report no. AX 73010; 1973b, (Unpublished).

    Somerville, L. and Hughes, K.W. Residue analyses of amitraz and its
    metabolite BTS 27271 on French peach crops (Report no. 2). Boots Co.
    Ltd. report no. AX 73013; 1973c, (Unpublished)

    Somerville, L. and Hughes, K.W. Residue analyses of amitraz and its
    metabolite BTS 27271 on Dutch apple crops. Boots Co. Ltd. report no.
    AX 73014; 1973d, (Unpublished).

    Somerville, L. and Hughes, K.W. The conversion of BTS 27419 to BTS
    27271 in the dog stomach. Unpublished report no. AX 73021; 1973e, from
    The Boots Company submitted to WHO.

    Somerville, L. and Hughes, K.W. Residue analyses of amitraz and its
    metabolite BTS 27271 on French apple crops. Boots Co. Ltd. report no.
    AX 73016; 1973f, (Unpublished).

    Somerville, L. and Nicholson, J.E. Amitraz. Metabolism in apples,
    variety Cox's Orange Pippin. Boots Co. Ltd. report no. AX 72003; 1972,
    (Unpublished).

    Somerville, L. and Richards, M.E. The analysis of fruit for combined
    residues of amitraz and BTS 27271. Boots Co. Ltd. report no. AX 80002;
    1980, (Unpublished).

    Somerville, L. and Spiers, M.J. Amitraz. Metabolism in apple leaves.
    Boots Co. Ltd. report no. AX 72002; 1972, (Unpublished).

    Sutton, M.M., RD 27271. Acute oral toxicity to mice. Unpublished
    report no. PM 70043; 1970a, from The Boots Company submitted to WHO.

    Sutton, M.M. RD 27271. Acute toxicity to rats. Unpublished report no.
    PM 70042; 1970b, from The Boots Company submitted to WHO.

    Sutton, M.M. Acaricides: RD 27419 and RD 27271 acute toxicity to
    guinea pigs. Unpublished report no. PM 70108; 1970c, from The Boots
    Company submitted to WHO.

    Sutton, M.M. BTS 27419. Contact sensitization in the guinea pig.
    Unpublished report no. PM 71010; 1971, from The Boots Company
    submitted to WHO.

    Sutton, M.M. BTS 27419: Effect on thermo-regulation in mice.
    Unpublished report no. P 72609; 1972a, from The Boots Company
    submitted to WHO.

    Sutton, M.M. BTS 27271: acute oral toxicity to rabbits. Unpublished
    report no. TXM 72044; 1972b, from The Boots Company submitted to WHO.

    Sutton, M.M. BTS 27419: Teratogenicity in the rabbit. Unpublished
    report no. TX 73029; 1973a from The Boots Company submitted to WHO.

    Sutton, M.M. BTS 27419: Teratogenicity in the rat. Unpublished report
    no. TX 73028; 1973b, from The Boots Company submitted to WHO.

    Sutton, M.M. BTS 27419: Effects on pregnancy, parturition and care of
    the young in rate. Unpublished report no. TX 73031; 1973c, from The
    Boots Company submitted to WHO.

    Sutton, M.M. BTS 27419: Multigeneration feeding test in rats.
    Unpublished report no. TX 73036; 1973d, from The Boots Company
    submitted to WHO.

    Sutton, M.M. BTS 27419: Three-week dermal toxicity to rabbits.
    Unpublished report no. TX 73026; 1973e, from The Boots Company
    submitted to WHO.

    Sutton, M.M. and Metcalf, W. BTS 27419. Eye-irritancy in the rabbit.
    Unpublished report no. TXM 72037; 1972, from The Boots Company
    submitted to WHO.

    Sutton, M.M. and Offer, J. BTS 27419: carcinogenicity and long-term
    toxicity study in rats. Unpublished report no. TX 73043; 1972, from
    The Boots Company submitted to WHO.

    Sutton, M.M. and Williams, G.A.H. BTS 27419: 90-day toxicity study in
    rate. Unpublished report no. P 71548; 1971, from The Boots Company
    submitted to WHO.

    Sutton, M.M. and Williams, P.A. BTS 27419: acute dermal toxicity to
    rabbits. Unpublished 1972 report no. YM 72011; 1972 from The Boots
    Company submitted to WHO.

    Taylor, J. and Somerville, L. The conversion of amitraz to BTS 24068
    in dog gastric juice. Unpublished report no. AX 77010; 1977, from The
    Boots Company submitted to WHO.

    Toyoshima, S., Fujita. H., Sato, H., Sato. R., Sato, S. and Kashima,
    M. JA-119 (BTS 27419). Three-month feeding study on rats. Unpublished
    report E 76014; 1972a, from The Boots Company submitted to WHO.

    Toyoshima, S., Fujita H., Sato, H., Sato, R., Sato, S. and Kashima, M.
    JA-119 (BTS 27419). Three month feeding study on mice. Unpublished
    report no. K 76015; 1972b, from The Boots Company submitted to WHO.

    Tuplin, J.A. and Wilcox, A. Amitraz. Ames-tests on a sample produced
    by Nissan Chemical Industries. Unpublished report no. TX 78068; 1978,
    from The Boots Company submitted to WHO.

    Weisburger, E.K. et al. Testing of twenty-one environmental aromatic
    amines or derivatives for long-term toxicity or carcinogenicity. J.
    Environ. Path. Toxicol. 2, 325-356.

    Wilcox, P. BTS 27419: Mutagenicity study in the intraperitoneal
    host-mediated assay. Unpublished report no. TX 76028; 1976, from The
    Boots Company submitted to WHO.

    Wilcox, P. Amitraz impurity BTS 33220: in vitro bacterial
    mutagenicity testing. Unpublished report no. TXA 79025; 1979, from The
    Boots Company submitted to WHO.

    Zimmer, D.M., Mazurek, J.H. and Bhuyan, B.K. Evaluation of amitraz
    (U-36.059) and its metabolites in the Salmonella microsome test.
    Unpublished report no. 72068/77/7269/002; 1977, from The Boots Company
    submitted to WHO.
    


    See Also:
       Toxicological Abbreviations
       Amitraz (ICSC)
       Amitraz (Pesticide residues in food: 1983 evaluations)
       Amitraz (Pesticide residues in food: 1984 evaluations)
       Amitraz (Pesticide residues in food: 1984 evaluations)
       Amitraz (JMPR Evaluations 1998 Part II Toxicological)