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    BUPROFEZIN

    First draft prepared by Dr. Otto Meyer,
    National Food Agency,
    Copenhagen, Denmark

    EXPLANATION

         Buprofezin, 2-tert-butylimino-3-isopropyl-5-phenylperhydro-1,3,5-
    thiadiazine-4-one is an insect growth regulator with high activity
    against homopterous insects. The substance acts by inhibiting chitin
    biosynthesis and subsequent cuticle deposition. It also has effects on
    hormone levels of nymphs associated with moulting. In addition this
    compound suppresses the egg-laying in female adults with incidental
    inhibition of prostoglandin synthesis.  Buprofezin is being reviewed
    for the first time at this meeting.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

         14C-Buprofezin, labelled in the phenyl ring and dissolved in
    olive oil was administered by gavage at a dose 10 or 100 mg/kg bw (5
    Ci/rat) to 4 and 3 Sprague-Dawley (SD) male rats, respectively (mean
    weight 200 g). Blood was taken from the tail vein 30 minutes and every
    hour up to 96 hours after dosing. Radio-activity was detected 30
    minutes after dosing (0.122 gram and 0.976 gram buprofezin
    equivalent per ml for 10 mg and 100 mg doses, respectively).  Maximum
    level (Cmax) of radioactivity was reached 9 hr post-dosing.  The Cmax
    was 1.2 and 13.3 gram buprofezin eq/ml for 10 and 100 mg, 
    respectively. The biological half lives were 13 hours (9-24 hours)
    after dosing and 60 hours (24-96 hours after dosing) irrespective of
    the dose. Total radioactivity in blood was calculated to be 0.82 and
    0.98% of 10 and 100 mg/kg dose, respectively (Sugimoto, 1982).

         Male SD rats (4 groups of 5) weighing 200 g were dosed with 10 or
    100 mg 14C-Buprofezin/kg b.w. (5 Ci/animal) as in the above study.
    The rats were sacrificed 2, 5, 9, 24 or 96 hours after dosing. 
    Following administration of the 10 mg/kg bw dose; the highest
    radioactivity was detected in the urinary bladder (14.27 gram
    equivalent/g) 9 hours post-dosing. Cmax in the liver was 11.6 gram
    eq/g after 5 hours.  Other organs and tissues with Cmax higher than
    1 gram were adipose tissue, kidney, adrenal gland, pancreas and blood
    (4.2, 2.5, 2.3 1.3 and 1.0 g equivalent/g respectively). Cmax of all
    tissues and organ occurred at 5-9 hours.  Following administration of
    100 mg/kg bw, the highest radioactivity was found in adipose tissue
    (114.7 g equivalent/g after 9 hours).  The distribution pattern was
    similar to that in the animals dosed at 10 mg, the level being 10
    times higher. The Cmax in liver, urinary bladder, adrenal gland
    kidney, pancreas and spleen were 85, 71, 47, 36, 33 and 33 g
    equivalent/g, respectively. The radioactivity in all tissues and
    organs was below 10 g equivalent/g or ml 96 hours post-dosing.  The
    t in all tissues and organs examined was 3.5-15 hours (between 9
    and 24 hours after dosing) and 15-72 hours (between 24 and 96 hours). 
    The radioactivity in blood, kidney and liver decreased relatively
    slowly between 24 and 96 hours after dosing (t was 37-72 hours)
    (Sugimoto, 1982).

         Five male SD rats were dosed with 14C-Buprofezin as in the above
    study, and sagittal sections taken  at 2, 5, 9, 24 and 96 hours after
    administration of 10 mg/kg bw (20 Ci/animal).  After 2 hours most the
    radioactivity was found in the alimentary canal.  The small amount of
    radioactivity detected in liver and kidney indicated that absorption
    and excretion had already begun. The level of radioactivity in tissues
    peaked after 5 and 9 hours. The levels of radioactivity at 9 hours
    were as follows: intestine > stomach > liver > kidney > lung,

    brown adipose tissue and blood > skin and thymus> thyroid > heart
    > muscle > brain > testis > bone marrow > eyeball. At 96 hours,
    radioactivity in the body was below 4% (Intestine > liver > kidney
    > skin > lung > blood). The levels of radioactivity in liver and
    intestine suggest the existence of enterohepatic circulation.  The
    radioactivity in kidneys was always less than that in liver (Sugimoto,
    1982).

         SD male rats 6 weeks of age (a total of 27/group) were given
    diets containing 200 or 1000 ppm buprofezin (purity: 99%) for up to 24
    weeks.  At 200 ppm, the concentrations in adipose tissue were 0.6-0.9
    ppm.  Less than 0.1 (the limit of detection) to 0.2 ppm was found in
    the liver and less than 0.1 ppm in other tissues. The corresponding
    figures for the 1000 ppm diet were 3.4, 0.2-0.3 and less than 0.1 ppm.
    The results indicate that buprofezin does not accumulate in tissues
    (Sugaya & Uchida, 1990).

         Male SD rats weighing 160-170 g were dosed with 14C-buprofezin
    as in the previous studies.  Ten mg and 100 mg/kg bw was administered
    to 2 and 3 rats, respectively (2 Ci/animal).  At the low dose, 82% of
    the radioactivity was excreted within 24 hours and 93% within 48
    hours.  At 100 mg/kg bw, 91% was excreted within 48 hours.  Totals of
    74% and 70% were excreted in faeces within 4 days for the low and high
    dose levels, respectively.  The corresponding figures for the urinary
    excretion were 22 and 25%, respectively. The excretion of radioactive
    CO2 into expired air was 0.21% in each dose.

         Ten mg 14C-buprofezin/kg bw (20 Ci/animal) was orally
    administered to 2 cannulated SD male rats weighing 210 g, and bile was
    collected from the bile duct for 24 hours. 38.41 and 31.66% of the
    dose was excreted into the bile in the two rats respectively
    (Sugimoto, 1982).

         Male and female SD rats weighing 160-240 g,  5/sex/dose received
    a single oral dose of 10 or 100 mg 14C-buprofezin/kg bw (0.6-0.7 ml
    corn oil/animal, 9.9-12 Ci/animal).  Urine and faeces were collected
    at 6 and 24 hours and thereafter at 24 hour-intervals for the
    subsequent 144 hours. Expired air was examined 0-6, 6-24 and 24-48
    hours after dosing in 1 male and 1 female per dose level.  Blood and
    tissues were analyzed at the end of the study.  The main route of
    elimination was via the faeces. Most of the elimination via urine and
    faeces took place within 48 hours. In male rats, 90-91% was eliminated
    in this period;  20-21% in urine and 69-71% in faeces. The
    corresponding figures for females were 87-89%, 13-14% and 73-76%,
    respectively. Very little radioactivity (less than 0.5%) was found in
    expired air. Elimination in males was faster than that in females in
    the first 24 hours but fairly even by 48 hours post dose. The highest
    concentrations were found in liver, thyroid and blood cells at both
    dose levels. (1.8-2.4 g eq./g and 0.1-0.4 g eq, per g for high and
    low dose respectively).  A mean of less than 0.7% of the dose remained

    in the body at sacrifice at both dose levels with liver constituting
    less than 0.2% of the total, intestine including contents less than
    0.04% and other tissues less than 0.01% (Caley & Cameron, 1988).

         Bile duct cannulated rats, 3 of each sex (see above study) were
    dosed with 10 mg 14C-buprofezin as above. Bile was collected frozen
    at hourly intervals up to 6 h and then hourly by fraction collected up
    to 24 h post-dosing.  Urine and faeces were collected separately for
    the periods 0-6 and 6-24 h. GI-tract, liver and residual carcass were
    analyzed at the end of the study. Total radioactivity equivalent to a
    mean of approximately 30% of the dose for males and 38% for females
    was recovered in bile 24 h post dosing.  Elimination via the urine
    accounted for a mean of 5.4% of the dose for males and 2.6% in
    females.  The corresponding figures for faeces were 34% and 19%,
    respectively. The radioactivity accounted for in GI-tract, liver and
    residual carcass was 16.6 and 27.5%, 1.0 and 1.5% and 3.8 and 3.2% for
    males and females respectively (Caley & Cameron, 1988).

    Biotransformation

         Urine, faeces and bile excreted within 24 hours were obtained for
    TLC analysis from male SD rats weighing 220-230 g administered a
    single peroral dose of 10 mg 14C-buprofezin/kg bw (20 Ci/animal).
    Faecal and urine of 3 rats were examined.  Faeces and bile were
    examined from 2 rats administered 2 Ci/animal. For solvent
    fractionation and identification of metabolites, urine and faeces
    obtained from 2 rats administered a single peroral dose of 100 mg/kg
    bw (10 Ci/animal) and 12 rats dosed with unlabelled material were
    used.  Hydroxylation of phenyl ring and oxidation of sulfur were the
    main routes of metabolism. Hydroxylation of phenyl ring gave
    4-hydroxy, 3,4-dihydroxy and 3-hydroxy-4-metoxy buprofezin and some of
    these were conjugated with glucuronic acid or sulfate.  The oxidation
    products of sulfur were thought to form isopropyl phenyl urea through
    the cleavage of the thiadiazin ring. Twelve percent of the dose was
    excreted into faeces as parent compound.  In urine and bile only more
    polar metabolites were detected.  In rats whose bile ducts had been
    cannulated, more than 95% of radio-activity in faeces was composed of
    the parent compound.  This indicates that buprofezin itself does not
    change in the intestinal tract. Glucoronides found in bile were not
    all detected in faeces. Moreover, metabolites in bile were not all
    found in faeces, and different metabolites which could not be detected
    in bile were found in faeces. Thus bile metabolites are further
    metabolized in the intestinal tract to form metabolites found in
    faeces.

         14C-Buprofezin (0.3 Ci) 4ml 4 g was added to rat liver
    homogenate (SD, male, average bw: 205 g), and incubated at 350 for 2
    hours, with and without S-9 and co-factors (NADH, NADPH, NADP, G6P
    dehydrogenase, G6P, MgCl2 and KCl).  The results indicated the same
    metabolic route as in the above  in vivo study However, isopropyl

    phenyl urea was only found in vitro and is probably further
    metabolized  in vivo (Sugimoto, 1982).

         The profile of metabolites in urine, faeces and bile was
    investigated in pooled samples from SD rats weighing 160-240 g
    administered one single oral dose 14C-buprofezin (faeces and urine
    from 5 rats/sex/group dosed 10 or 100 mg/kg bw; faeces and urine from
    1 male and 1 female, bile duct cannulated, dosed 10 mg/kg bw and bile
    from 1 male and 1 female, bile duct cannulated, dosed 10 mg/kg bw
    (Caley & Cameron, 1988).  TLC of urine and bile indicated extensive
    conjugation, and only a small amount of buprofezin co-chromatographing
    material was found in the urine in one sample. Faecal extracts
    indicated conjugated material and components co-chromatographing with
    2-tert-butylimino-3-isopropyl-5-(4-hydroxy-phenyl) perhydro-1,3,5-
    thiadiazin-4-one (a minimum of 1.76% and 0.38% of the administered
    dose for high and low dose respectively) and possibly with
    2-tert-butylimino-5-(3,4-dimethoxyphenyl)-3-isopropyl-3,4,5,6-tetrah
    ydro-2H-1,3,5,-thiadiazin-4-one and with buprofezin (a minimum of
    7.99% and 10.24% of the administered dose for the high and low dose
    respectively). Faecal extracts of the bile duct cannulated rats showed
    only radioactivity co-chromatographing with buprofezin. The possible
    intestinal deconjugation of metabolites from bile may be attributable
    to microorganisms in the intestine (Caley & Cameron, 1988).

         Polar metabolites in faeces and urine from rats administered
    single oral doses of 10 or 100 mg 14C-buprofezin/kg bw were studied.
    Sulfuric acid conjugates of 1-(4-hydroxyphenyl)-3-isopropylurea,
    p-aminophenol and p-acetamidophenol were identified. Sulfuric acid
    conjugate of p-acetamidophenol was the major metabolite in urine,
    accounting for 3.9% of the dose (Sugimoto  et al., 1982).

         In faeces, the sulfuric acid conjugate of p-acetamidophenol
    accounted for 2.7% of the dose (Uchida 1988.)

    Toxicological studies

    Acute toxicity studies

         The acute toxicity of buprofezin is shown in Table 1.


        Table 1.  Acute toxicity of buprofezin

                                                                                                      

    Species       Sex        Route            LC50          LC50       Reference
                                           (mg/kg/bw)      (mg/l)
                                                                                                      

    Mouse         M&F        oral           > 10 000           -       Ebino & Shirasu (1981a)
                             i.p.           > 10 000           -       Ebino & Shirasu (1981a)
                             s.c.           > 10 000           -       Ebino & Shirasu (1981a)

    Rat           Ma         oral               2198           -       Ebino & Shirasu (1981b)
                  Fa                            2355
                  Mb         oral               1635           -       Tsuchiya & Sugimato (1982)
                  Fb                            2015
                 M&Fa        i.p.           > 10 000           -       Ebino & Shirasu (1981b)
                 M&Fa        s.c.           > 10 000           -       Ebino & Shirasu (1981b)
                 M&Fa       dermal            > 5000           -       Ebino & Shirasu (1981b)
                 M&Fa     inhalation               -         > 4.6     Tsuda (1984)
                          (4 h. exp.)

    Hamster       Mc         oral           > 10 000           -       Tsuchiya & Sugimato (1979b)

    Rabbit        Md         oral             > 5000           -       Tsuchiya & Sugimato (1979c)

         Buprofezin of greater than 99% purity was used.
                                                                                                      

    a SPF Fischer strain    c  Golden hamsters
      SPF ICR strain        d  Japanese albino
    b SD rats
    

    Short-term studies

    Rats

         Groups of Sprague-Dawley rats (Jcl: SD), 5 weeks of age received
    buprofezin (purity: >99%) in the diet for 90 days at concentrations
    of 0, 40, 200, 1000 or 5000 ppm (10 animals/sex/group).  The actual
    concentrations were 46, 185, 982 and 4555 ppm;  the compound was shown
    to be stable up to 18 weeks after mixing.  All animals were observed
    daily for clinical signs and mortality.  Body weights and food
    consumption were recorded weekly. In the 13th week, daily water intake
    and urine volume were recorded and urinalysis performed. 
    Haematological examinations (on day 90) and assessment of blood
    chemistry at terminal sacrifice were performed.  Gross pathological
    examination was performed on all animals at necropsy and selected
    organs were weighed.

         No effects on mortality nor clinical appearance were observed. 
    Body weight gains were suppressed in males and females at 5000 ppm and
    in females at 1000 ppm.  Food intake was slightly lowered in the 200,
    1000 and 5000 ppm groups, but feed efficiencies were not affected.
    Water intake was significantly increased in top dosed males. 
    Haematocrit, haemoglobin and red blood cell count in top-dosed males
    and haematocrit in top-dosed females were decreased.  Activated
    partial thromboplastin times were prolonged in the 5000 ppm group.  In
    animals receiving the 5000 ppm diet, serum glucose and triglyceride
    concentrations were lowered and the concentrations of total
    cholesterol and phospholipids were elevated. In males at this level,
    there were increases in serum beta-globulin, alpha 1-globulin and
    albumin and a decrease in gamma-globulin.  In females at the highest
    dose level,  an increase was recorded in albumin, alpha 1-globulin,
    alpha 2-globulin, alpha 3-globulin and beta-globulin.  Serum glucose
    was lowered in males dosed at 200 ppm and above and beta-globulin and
    alpha 1-globulin was elevated in females receiving 1000 ppm.  Both
    absolute and relative liver and thyroid weights were increased at 5000
    ppm.  In the 1000 ppm group, the relative thyroid weight was increased
    in males and relative liver weight in females.  Enlargement of the
    hepatocytes in the central to the middle zone of the lobules and
    thickening and hyperplasia of the follicular epithelial cells of the
    thyroids were observed in top-dosed animals and in some animals in
    1000 ppm group.  No compound-related adverse effects were observed at
    40 ppm in the diet, equivalent to 3.4 mg/kg bw/day for males and 4.1
    mg/kg bw/day for females (range 5.7-2.5 mg/kg bw/day and 5.8-3.2 mg/kg
    bw/day for males and females respectively).  The liver and thyroid
    were identified as target organs.  The NOAEL was 40 ppm (Watanabe,
    1986).

    Dogs

         Beagle dogs, 15-17 weeks of age (4/sex/group) received buprofezin
    (purity: 99.0%) orally in gelatin capsules at dosages of 0, 2, 10, 50

    or 300 mg/kg bw/day for 13 weeks.  Individual observations of all
    animals and food consumption were recorded daily. Water consumption
    was measured twice before commencement and during weeks 4, 8 and 13 of
    treatment. Each animal was weighed before feeding and weekly during
    the treatment period. Clinical examination was performed before
    commencement and after 4, 8 and 12 weeks of treatment. 
    Ophthalmo-logical examination on each dog was carried out before
    commencement and after 12 weeks of treatment.  Blood was sampled
    before commencement, and after 6 and 12 weeks of treatment for
    haematology and blood chemistry. Overnight urine was also collected on
    the same sample schedule as blood sampling for urine analysis. On
    completion of the treatment period, all dogs were sacrificed and
    subjected to necropsy. Organ weights were recorded and 
    histopathological post-mortem examination was performed.

         No mortalities were observed during the study. Subdued behavior
    was seen in the 50 and 300 mg/kg/day dose groups and signs of slight
    ataxia and slight abdominal distension were noted in the 300 mg/kg/day
    dose group. Food consumption and body weight gains of dogs receiving
    300 mg/kg/day were lower than controls. Water consumption of one
    high-dose female was reduced during the treatment.  No treatment-
    related effects were revealed by clinical nor ophthalmological
    examination.  A slight increase in prothrombin times was seen in
    females receiving 300 mg/kg/day. No effects of treatment were apparent
    on haematological parameters. Plasma alkaline phosphatase activity was
    raised in males receiving 50 mg/kg/day and in all dogs receiving 300
    mg/kg/day.  The normal decline in alkaline phosphatase activity with
    maturity was less evident in animals receiving 10 mg/kg/day and in
    females dosed at 50 mg/kg/day. Slightly elevated alanine
    aminotransferase activity was recorded in dogs receiving 300
    mg/kg/day.  No treatment-related effects were noted in urine analysis. 
    The following changes in absolute and relative organ weights were
    noted; high liver weight in one male receiving 2 mg/kg/day, two males
    receiving 10 mg/kg/day, all dogs receiving 50 or 300 mg/kg/day, high
    kidney weight in dogs receiving 300 mg/kg/day, high thyroid weight in
    males receiving 50 mg/kg/day and males and females receiving 300
    mg/kg/day.  However, the changes of liver weight in the 2 and 10
    mg/kg/day dose groups were considered to be of no toxicological
    significance. At necropsy no treatment-related lesions were noted. 
    Homogeneity of cytoplasm and intracytoplasmic eosinophilic bodies in
    the hepatocytes were seen in dogs receiving 50 or 300 mg/kg/day.  The
    NOAEL for this study was 10 mg/kg/day based on changes in the liver
    (Broadmeadow, 1986).

         Beagle dogs (6/sex/group), 16-17 weeks of age were administered
    0, 2, 20 and 200 mg/kg bw/day of buprofezin (purity, >99%) by oral
    gelatin capsules for 107 weeks. Body weight, food consumption and
    clinical observations were recorded. Ophthalmoscopy was performed
    prior to the test and during the dosing period.  Smears of bone marrow
    were obtained by biopsy at week 104 of treatment. During week 104 of
    treatment, alkaline phosphatase isozymes were separated by

    electrophoresis, and determined densitometrically.  Blood samples were
    taken from each dog before, and periodically during the experiment to
    examine thyroid function, haematology and clinical chemistry. After 53
    and 103 weeks of treatment, BSP excretion test was conducted for
    assessment of liver function. At week 107 all dogs were subjected to
    pathological examination.

         There were no effects of treatment on mortality or clinical signs
    (including ophthalmoscopy) of toxicity. Body weight gain was
    suppressed for dogs receiving 200 mg/kg bw/day, and food consumption
    was marginally lower in top-dosed males when compared to controls. 
    Apart from occasional increases in mean cell volume and mean cell
    haemoglobin in males receiving 20 and 200 mg/kg bw/day, no effect of
    treatment on haematology (peripheral blood and bone marrow) nor
    urinalysis was noted.  Increased plasma alkaline phosphatase activity
    was seen in animals in high and intermediate dose groups, and an
    increase in plasma alanine amino-transferase activity was recorded in
    top-dosed animals. Reduced serum thyroxin was noted in dogs receiving
    the high dose, while tri-iodothyronine and protein bound iodine
    concentrations were unaffected.  BSP (bromsulfophthalein) retention
    after 103 weeks of treatment was increased in females receiving 20 or
    200 mg/kg bw/day.  Both absolute and relative liver and thyroid
    weights were increased in top-dosed females and relative liver and
    thyroid weight was increased in top-dosed males. Absolute liver weight
    was elevated in females dosed with 20 mg/kg bw/day, and the relative
    liver weight was increased in females in all dosage groups.  No
    treatment-related changes were noted in macroscopic examination. 
    Microscopic examination revealed enlargement of centrilobular
    hepatocytes and bile duct hyperplasia in the liver of dogs receiving
    20 and 200 mg/kg bw/day.  The NOAEL of buprofezin administered orally
    to dogs over a period of 2 years is 2 mg/kg bw/day (Cummins, 1982).

    Long-term/carcinogenicity studies

    Mice

         In an oral long-term toxicity and oncogenicity study, groups of
    70 male and 70 female SPF ICR mice (Crj: CD-1), 5 weeks of age were
    exposed to buprofezin (purity: 99.5%) as a dietary admixture at
    concentrations of 0, 20, 200, 2000 or 5000 ppm, equivalent to 0, 1.8,
    17, 190 and 481 mg/kg bw/day for males and 0, 1.9, 18 191 and 493
    mg/kg bw/day for females for 104 weeks. Satellite groups of 10
    animals/sex/group were treated in a similar manner for 52 weeks. 
    Analysis of the diet showed that the test compound was stable at
    ambient conditions for one month.  Determination of concentration and
    homogeneity of test compound in the diet was made at intervals of
    three months.  Diet analysis revealed satisfactory consistency in
    concentration and homogeneity of the test compound.  Ten animals of
    each sex/group were subjected to urinalysis, haematology and blood
    chemistry and sacrificed for pathological examinations at week 52 and
    104. Gross pathological examination was performed on all animals.

    Organ weights were recorded in each animal subjected to interim or
    terminal kill.

         In the 5000 ppm group, retarded growth, decreased specific
    gravity of urine, reduced levels of protein in the urine, elevation in
    platelet and lymphocyte count (after 104 weeks of treatment),
    increased absolute and relative liver weight and an increased
    incidence of hepatocellular swelling (centrilobular and diffuse) and
    hepatocellular hyperplasia were seen in both sexes. The total blood
    cholesterol was increased at week 52 for females and week 104 for
    males.  In the 2000 ppm group, slightly retarded growth and an
    increased incidence of centrilobular hepatocellular swelling were
    recorded in both sexes.  The absolute and relative liver weights were
    increased in both sexes in the same animals after 52 weeks.  An
    increased incidence of hepatocellular hyperplasia was observed in
    females.  In the 200 ppm group an increase in liver weight was noted
    in males at week 52.  The incidence of hepatocellular adenoma was
    increased in top-dosed females, but the combined incidence of these
    adenomas and hepatocellular carcinomas was not statistically
    significantly different from controls (12/80 and 5/80, respectively). 
    However, the denominator should be 70, as no tumours were found at 52
    weeks.  The overall incidence of lung adenoma and carcinoma in males
    of the 200 and 5000 ppm groups were significantly higher than those of
    the controls.  The combined incidences were 30/80, 23/80, 29/80, 26/80
    and 17/80 for 5000, 2000, 200, 20 and 0 ppm, respectively.  Adenomas
    were seen in dosed animals in an incidence of 2/10 after 52 weeks
    compared to 0 in controls.  The incidence of hepatocellular carcinoma
    in the females receiving 2000 and 5000 ppm, 4/80, falls outside the
    historical range of 0/80-3/80.  However, the control incidence was
    3/80. It is concluded that the data does not indicate a carcinogenic
    potential.  The NOAEL is 20 ppm (male) equal to 1.82 mg buprofezin/kg
    bw/day (Yoshida, 1983).

         In a long-term toxicity study, groups of 40 male and 40 female
    Jcl: SD rats, 5 weeks of age were exposed to buprofezin (purity:>99%)
    mixed in a powdered CE-2 chow in doses 0, 5, 20, 200 and 2000 ppm for
    24 months. Additional groups of 5 and 10 rats of each sex were exposed
    in a similar manner for 6 and 12 months respectively. Analysis of test
    diets showed that the actual concentrations were 3.9-6.5 ppm (first 2
    months, 12 ppm), 16.5-21 ppm (first 2 months, 26 ppm), 175-210 ppm and
    1700-2000 ppm (last 2 month, 2300 ppm) respectively. The compound was
    stable in the diet up to 120 days. The daily intake (total mean) of
    the test compound was equal to 0.26, 0.90, 8.71 and 89.46 mg/kg bw/day
    for males and 0.33, 1.12, 11.19 and 114.71 mg/kg bw/day for females. 
    Haematology, blood chemistry and urine analysis were performed at 6,
    12 and 24 months of treatment. Necropsy was performed on all animals
    including those found dead or killed in extremis.  Organ weights were
    measured at necropsy. Phenolsulfophthalein (PSP) and
    bromsulfophthalein (BSP) excretion tests were performed in 5 males and
    5 females from control and 2000 ppm groups at 24 month of treatment. 
    All animals were subjected to histopathological examination. Electron

    microscopic examination was performed on liver samples which showed
    treatment-related changes.

         No effect of treatment on clinical observations was observed, and
    survival in all groups was > 40%. Body weights were lowered in
    top-dosed animals of both sexes in the first months, and in addition
    in the females scattered during the last period of dosing.  No
    treatment-related changes were noted in food consumption, food
    efficiency, urinalysis, haematology, blood chemistry, PSP and BSP
    excretion test. Increased absolute and relative liver and thyroid
    weights were seen in males and females in the 2000 ppm group.  An
    increase in relative kidney and heart weights was noted in females
    dosed 200 and 2000 ppm at 24 months. Hypertrophy of hepatocytes was
    seen in males and females in the 2000 ppm group. The hypertrophy was
    associated with proliferation of smooth endoplasmatic reticulum by
    electron microscopy.  The incidence of hyperplastic nodules was
    slightly higher in the 2000 ppm group at 24 months.  Thickening and
    hyperplasia of the follicular epithelial cells in thyroids were
    observed in most of the animals in the 2000 ppm group and in a few
    animals in the 200 ppm group. In addition, increased incidence of
    cystitis, chronic nephrosis and interstitial oedema in the heart was
    observed in top-dosed females. No effect of treatment was observed on
    any type of tumour.  The NOEL was 20 ppm,  equivalent to 0.9 mg/kg
    bw/day and 1.12 mg/kg bw/day for males and females, respectively
    (Watanabe  et al., 1982.)

    Reproduction studies

         Groups of 30 male and 30 female Wistar-Imamichi rats (SPF),
    4 weeks of age (F0) were exposed to buprofezin (purity: 99.1%) in a
    pelleted diet in concentrations of 0, 10, 100 or 1000 ppm.  Analysis
    of the diets was reported to be satisfactory.  Data on stability of
    the chemical in the diet were not given.  Rats were dosed for 13 weeks
    before mating (1:1).  Ten days after weaning of F1a pups,  the F0
    were mated a second time to obtain F1b pups.  The resulting F1b pups
    from 10 pregnant dams in each group underwent teratological
    examination. F1b pups, 30 of each sex, from the remaining pregnant
    dams (born within 4 days) were selected for production of the F2
    generation.  The above procedure was repeated to produce F2 animals.
    Fifteen rats of each sex were selected from weaned F2b pups and
    reared for 12 weeks.  In each generation, the litters were reduced to
    8, 4 males and 4 females, on day 4 post-partum.  Observations in F1b
    and F2b pups included pinna unfolding, hair growth, incisor eruption
    and eye opening, righting reflex, pain reflex, auditory reflex,
    grasping reflex and posture and gait on day 21.

         The high-dose animals exhibited lower body weight gain compared
    to the controls;  this was most pronounced in F1 and F2 males.
    Depressed weight gain was also seen at lower doses, especially in F1
    animals the first weeks after weaning. No consistent effect was

    observed in food and water consumption.  The actual compound intakes
    were determined to be 0.6-0.8, 6-8.1 and 62.5-86.5 mg/kg bw/day for
    males and 0.8-0.9, 7.9-8.9 and 82.6-85.2 mg/kg bw/day for females in
    the low, medium and high dose-groups, respectively.  Litter data
    revealed a decrease in survival of F0 pups during day 0-4 of the
    lactation period in 10 and 1000 ppm group and lower mean live pups
    weight in all dosed groups (first mating), a decrease in number of
    delivered and live pups in 100 and 1000 ppm groups from F1 2nd mating
    (F2b), and a decrease in body weights of the pups during lactation in
    top-dose, most pronounced in F1a and F2a animals, and in all
    dose-groups in F2a. Decreased fetal weight was seen in second mating
    of F0 (F1b) but not in the analogous F2 animals.  The absolute
    liver weight was increased in high-dose females in F0 and F1 and in
    F1 males, while the relative liver weight in the same group was
    increased in females in all generations and in males in all
    generations except the F0.  At doses up to 1000 ppm buprofezin has
    no influence on reproductive performance in rats (Takeshima, 1982).
    However, the study does not clearly indicate a NOAEL for decreased
    body weight gain.

         Groups of 25 Wistar-Imamichi rats, 4 weeks of age (F0) were
    exposed to buprofezin (purity: 99.1%) in a pelleted diet in
    concentrations 0, 10, 100 or 1000 ppm (chemical analysis of the diet
    reported satisfactory) in a study design similar to the above study
    (however, no examination for teratological effects was performed). The
    study was initiated as an additional study to the above and it is
    entitled "two-generation reproduction study". However, the study
    design is of a one-generation study with 2 litters in the
    F1-generation.  The actual dose for males was measured as 0.6, 6.4
    and 65.6 mg/kg bw/day and for females 0.9, 8.9 and 82.8 mg/kg bw/day
    in the low, medium and high dose groups.  Decreased body weights
    during lactation were observed in F1 pups of both sexes in the 1000
    ppm group.  Relative liver weight was increased in top-dosed animals. 
    The NOAEL is 100 ppm, equal to 6.4 and 8.9 mg/kg bw/day for males and
    females, respectively (Takeshima  et al., 1985).

    Special studies on teratogenicity and embryotoxicity

    Rats

         Four groups of 22 mated CD female rats (of Sprague-Dawley
    origin), 8 to 10 weeks of age were dosed with buprofezin (purity:
    99.0%) in 2% (w/v) aqueous gum arabic mucilage by oral gavage at doses
    of 0 (vehicle), 50, 200 or 800 mg/kg bw/day from day 6 to day 15 of
    gestation inclusive (dosage volume: 10 ml/kg bw). Samples of each
    concentration of the test mixtures taken during first and last weeks
    of treatment showed that the low, medium and high level dose were
    38.3-37.3, 188-166 and 776-819 mg/kg bw/day.  Maternal toxicity was
    evidenced by reduced food intake, decreased body weight, loose faeces,
    urogenital staining, lethargy, hunched posture, thin appearance and

    piloerection, only in top-dosed animals. A transient reduction in food
    intake was also recorded on day 14 of gestation in the group receiving
    200 mg.  Water consumption during the treatment period was
    significantly increased in the groups receiving 200 or 800 mg.  At 800
    mg/kg bw/day, 4 females showed total resorption and in females which
    carried live young to term, increased early post-implantation loss and
    reduced litter size and fetal weight were recorded.  Fetuses in the
    highest dosage group showed a significantly increased incidence of
    subcutaneous oedema and signs of slight fetal immaturity including
    reduced mean fetal weight. At 200 mg there was a slight reduction in
    the degree of ossification of supra-occipital and interparietal bones
    (within the ranges of historical control data) with other ossification
    parameters unaffected.  Treatment with buprofezin at dosages up to 800
    mg/kg bw/day did not give rise to any gross morphological changes
    (Tesh  et al., 1987).  The NOAEL was 50 mg/kg bw/day for maternal
    toxicity and less than or equal to 166 to 188 mg/kg bw/day for
    embryotoxicity.

    Rabbits

         Groups of 17 mated New Zealand White rabbits, 21-27 weeks old,
    were dosed with buprofezin (99% purity) in 2% (w/v) aqueous gum arabic
    by oral gavage at dosages  0, 10, 50, or 250 mg/kg bw/day from day 6
    to 19 of the gestation period inclusive (dosage volume: 5 ml/kg bw). 
    Samples of each concentration of the test mixtures taken during first
    and last weeks of treatment showed the low, medium and high doses were
    8.4-9.5, 51-46 and 231-224 mg/kg bw/day respectively.  Animals in the
    high dose group lost weight initially following onset of treatment,
    and overall body weight gain during gestation was reduced. Food
    consumption was reduced from the commencement of the treatment period
    until day 13 of gestation in the 250 mg-group, whereas water intake
    was unaffected. One female receiving 50 mg/kg bw/day aborted, and two
    females receiving 250 mg showed resorption of the entire litter. No
    other treatment-related effects were found.  Buprofezin at dose levels
    up to 50 mg/kg bw/day showed no adverse effect on either maternal
    condition or upon the progress and outcome of pregnancy, or upon fetal
    morphogenesis (Tesh  et al., 1986).

    Special studies on genotoxicity

         Buprofezin did not have mutagenic properties when tested in a
    number of  in vitro and  in vivo systems, which included assessment
    of gene mutations, DNA damage, and clastogenic effects.


        Table 2.  Summary of special studies on the mutagenicity of buprofezin

                                                                                                                            

    Test system                      Test object            Concentration          Purity      Results       Reference
                                                            of buprofezin
                                                                                                                            

    Ames test (with and              S. typhimurium         10-5000                99.3%       Negative      Moriya (1980)
    without metabolic                TA98, TA100,           g/plate                           (1)
    activation)                      TA1535, TA1537,        dissolved in
                                     and TA1538             DMSO

    Reverse mutation (with           E. coli WP2 uvr A      10-5000                99.3%       Negative      Moriya (1980)
    and without metabolic                                   g/plate                           (1)
    activation)                                             dissolved in
                                                            DMSO

    Ames test (with and              S. typhimurium         1.6-5000               99.8%       Negative      Callander (1988)
    without metabolic                TA98, TA100,           g/plate                           (2)
    activation                       TA1535, TA1537         dissolved in
                                     and TA 1538            DMSO

    Mouse lymphoma forward           Mouse L5178Y           13.3-100 g/ml         99.8%       Negative      Cross (1988)
    mutation assay (with             TK +/- cells           dissolved in                       (3)
    and without metabolic                                   DMSO
    activation

    DNA repair assay (with           B. subtilis            20-5000 g/disk        99.3%       Negative      Moriya (1980)
    and without metabolic            H17 & M45              dissolved in                       (4)
    activation)                      (rec +/-)              DMSO

    In vitro cytogenetics            Human                  10, 60 and 100         99.8%       Negative      Howard &
    (with and without metabolic      lymphocytes            g/ml dissolved                    (5)           Richardson
    activation)                                             in DMSO                                          (1988)
                                                                                                                            

    Table 2 (contd).

                                                                                                                            

    Test system                      Test object            Concentration          Purity      Results       Reference
                                                            of buprofezin
                                                                                                                            

    Unscheduled DNA synthesis        Primary hepatocytes    10-9-10-3M             99.8%       Negative      Trueman (1988)
                                     from male. Alpk:       dissolved in                       (6)
                                     APfSD rats             DMSO

    Mouse micronucleus test          BDF1 mice              6400, 8000 and         99.5%       Negative      Sasaki (1983)
                                                            10 000 mg/kg                       (7)
                                                            (administered orally
                                                            single or 4 times)
                                                                                                                            

    (1)   The positive controls, 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide; AF-2, N-ethyl-N'-nitro-N-nitrosoguanidine,
          2-nitrofluorene, 9-aminoacridine and 2-aminoanthracene gave the expected positive results.
    (2)   The positive controls, acridine mutagen ICR191, 2-aminoanthracene, daunomycin hydrochloride, 4-nitro-o-phenylenediamine
          and N-methyl-N-methyl-N'-nitro-N-nitrosoguanidine gave the expected positive results.
    (3)   The positive controls, ethylmethanesulphonate and N-nitrosodimethylamine gave the expected positive results.
    (4)   The positive control, mitomycin C gave the expected positive results.
    (5)   The positive controls, mitomycin C and cyclophosphamide gave the expected positive results.
    (6)   The positive control, 6-p-dimethylaminophenylazobenthiazole gave the expected positive results.
    (7)   The positive control, mitomycin C gave the expected positive results.
    

    Special study on duodenal ulcer formation

         This study was performed in order to investigate in detail
    duodenal ulceration seen in the acute oral toxicity study of
    buprofezin in rats.  Groups of 10 male and 10 female SPF Fischer rats
    5 weeks of age were administered a single dose of buprofezin (purity:
    99.5%) at doses of 0, 613, 1036, 1751, 2959 or 5000 mg/kg by gavage
    (vehicle, olive oil, 1.2-10 ml/kg bw). Mortality and clinical signs
    were observed during 4 days after the treatment. The observation
    period was determined to examine the generation of duodenal ulceration
    in accordance with the results obtained from a previous pilot study.
    Body weight was recorded just before treatment, at death or at the end
    of the study. At day 4 all surviving animals were killed. All animals
    were subjected to necropsy and histopathological examination of the
    duodenum.  Four males and 8 females in the 2959 mg/kg group and 9
    males and 10 females in the 5000 mg/kg group were found dead or killed
     in extremis.  Tremor (in animals dosed at 613 mg/kg bw and 1036
    mg/kg bw or more) subdued behavior, diarrhoea, gait disturbance,
    piloerection, lacrimation, soiled fur, chromodacryorrhoea and eyelid
    closing (in animals dosed at 1751 g/kg bw or more) were observed.  At
    1751 mg/kg and above decreased body weight was shown in surviving
    animals. At necropsy there was congestion, red or white spots and/or
    perforated foci in the proximal duodenum in males treated at 2959
    mg/kg and above and in females at 1751 mg/kg and above.  There were no
    gross abnormalities in other tissues or organs of all treated animals.
    At histopathological examination, ulcerous lesions in the duodenum
    were detected in one male treated at 1751 mg/kg, in 5 males and 8
    females at 2959 mg/kg and in all males and females at 5000 mg/kg.
    These lesions were not observed in males treated at 1036 mg/kg and
    below nor in females treated at 1751 mg/kg and below.  The NOAEL of
    buprofezin for the formation of duodenal ulceration was 1036 mg/kg in
    males and 1751 mg/kg in females (Ueda, 1985).

    Special studies on thyroid function

         In male Sprague-Dawley rats treated orally with buprofezin for
    about one month, weight increase and morphological changes were
    observed in thyroid. Further studies were conducted to investigate the
    effects of Buprofezin on the thyroid function using rats (male S-D
    rats), mice (ddY mice), hamsters (golden), guinea pigs (Mortely) and
    rabbits (Japanese white) (number of animals not given).

         In male rats treated orally with buprofezin (purity: > 99%) at
    doses of 100, 300 or 1000 mg/kg/day (in olive oil, 5 ml/kg b.w.) for
    7 days, dose-related decreases in serum tri-iodothyronine (T3) and
    thyroxine (T4) concentrations were observed.

         Rats were fed a diet containing buprofezin in concentrations of
    200, 1000, or 5000 ppm propyl-thiouracil (PTU) for 1, 3 or 6 months.
    At 5000 ppm of buprofezin the levels of serum T3 and T4 decreased

    to 30% and 70% of each control level, respectively and then recovered. 
    No effects of buprofezin were observed in rats treated with buprofezin
    at 1000 ppm. In the rats treated with PTU, however, the decreases of
    the serum levels of T3 and T4 were more marked than those in rats
    treated with buprofezin at 5000 ppm and the recoveries of those
    thyroid hormone levels were not observed.

         Rats were dosed with 500 mg buprofezin/kg bw/day or 30 mg PTU/kg
    bw/day by oral gavage for 15, 30 or 60 days and sacrificed 24 hours
    after the final dose.  Body weight gain was strongly depressed by 15
    days after commencement of the treatment in buprofezin and PTU dosed
    rats. Both absolute and relative thyroid weights were increased in the
    treated groups when compared to the control group.  Serum T4 was
    lowered and thyroidal peroxidase activity was elevated in treated
    animals when compared to control.  For all the above parameters the
    changes in PTU dosed animals were more pronounced than those of the
    buprofezin dosed animals.  Vacuolation of cells in anterior pituitary
    was scored moderate to severe in buprofezin and PTU dosed animals,
    while that of the controls was graded normal to slight.

         In an  in vitro study of buprofezin, PTU and potassium cyanide,
    KCN (PTU and KCN are known inhibitors to thyroidal peroxidase
    activity) were added to a reaction mixture of thyroidal peroxidase. 
    No effect of Buprofezin was observed even at concentrations up to
    7.2 x 10-5 M (greater than aqueous solubility).

         A comparison of the effect of Buprofezin treatment on serum
    protein-binding iodine (PBI) in rats (0, 100, 300, 500 and 1000 mg/kg
    bw/day), mice (0, 100, 300, 500 and 1000 mg/kg bw/day), hamsters (0,
    300 and 500 mg/kg bw/day), guinea pigs (0, 300 and 500 mg/kg bw/day)
    and rabbits (0, 300 and 500 mg/kg bw/day) showed that the most marked
    decrease of serum PBI was observed in rats among the species tested.
    In guinea pigs and rabbits the decreases of serum PBI caused by
    Buprofezin were less than that in rats. No effects of Buprofezin on
    serum PBI were observed in mice and hamsters.

         In summary, buprofezin has a lower potency for thyroid inhibition
    than PTU and likely acts by a different mechanism.  The rat appears to
    be more sensitive to this effect than mice, hamsters, guinea pigs and
    rabbits (Konaka & Nokata 1989).

    Observations in humans

         The effects of buprofezin in humans have been reported by a
    manufacturer of technical material. Medical surveillance of workers
    who routinely handled buprofezin in a factory has been undertaken. The
    survey revealed no effects which could be attributable to exposure to
    buprofezin (Nokata, 1990).

    COMMENTS

         The toxicokinetics and metabolism of buprofezin have been studied
    in rats.  It is rapidly absorbed and excreted after oral
    administration.  After oral administration of 14C-buprofezin,
    radioactivity was widely distributed in the tissues.  After 48 hours,
    91-93% of the administered radioactivity had been eliminated, 70-80%
    via faeces and 22-25% via urine.  Up to 38% had been excreted in the
    bile after 24 hours.  Buprofezin is metabolized by hydroxylation of
    the phenyl ring and oxidation of sulfur.

         The acute oral toxicity of buprofezin was low in mice, rats,
    hamsters and rabbits.  WHO has classified buprofezin as "unlikely to
    present an acute hazard in normal use".

         In a 90-day study in rats, buprofezin was administered at dietary
    concentrations of 0, 40, 200, 1000 or 5000 ppm.  The NOAEL was 40 ppm,
    equal to 3.4 mg/kg bw/day for males and 4.1 mg/kg bw/day for females. 
    At higher concentrations an increase in organ weights and histological
    changes were noted in the liver and thyroid.

         In a 13-week study in dogs, buprofezin was administered orally in
    gelatin capsules at doses of 0, 2, 10, 50 or 300 mg/kg bw/day.  The
    NOAEL was 10 mg/kg bw/day.  Raised plasma alkaline phosphatase
    activity and elevated liver weights were seen at both higher doses.

         In a two-year study in dogs buprofezin was administered orally in
    gelatin capsules at doses of 0, 2, 20 or 200 mg/kg bw/day.  The NOAEL
    was 2 mg/kg bw/day.  Increased liver weight (associated with
    enlargement of centrilobular hepatocytes and bile duct hyperplasia)
    was seen at higher doses.

         Teratogenic studies in rats at doses of buprofezin of 0, 50, 200
    or 800 mg/kg bw/day and in rabbits at 0, 10, 50 or 250 mg/kg bw/day
    gave no indication of teratogenic potential.  The NOAEL for maternal
    toxicity in both species was 50 mg/kg bw/day.

         Two reproduction studies were performed in rats with buprofezin
    at dietary concentrations of 0, 10, 100 or 1000 ppm.  The first of
    these was a two-generation study in which no clear NOAEL could be
    identified for possible adverse effects upon pup-weight gain;
    consistent treatment-related effects were observed only at 1000 ppm in
    both litters of each generation.  No effects were noted in the F2
    generation that were not also present in the F1 generation.  The
    second study was a single-generation study in which there were two
    matings.  The only effects attributable to treatment were reproducible
    reductions in pup-weight gain at 1000 ppm.  The NOAEL in this study
    was 100 ppm, equal to 6.4 mg/kg bw/day and 8.9 mg/kg bw/day for males
    and females respectively.

         In a long-term/carcinogenicity study in mice at dietary
    concentrations of 0, 20, 200, 2000 or 5000 ppm the NOAEL was 20 ppm,
    equal to 1.82 and 1.89 mg/kg bw/day for males and females
    respectively.  Absolute liver weight was increased at 200 ppm and
    above.  The incidence of hepatocellular adenoma was increased in
    females at 5000 ppm.  There was an increased overall incidence of lung
    adenoma and carcinoma in males dosed at 200 and 5000 ppm, but not at
    1000 ppm.  However, the incidences were within the historical control
    range for the strain used.

         In rats fed dietary concentrations of 0, 5, 20, 200 or 2000 ppm
    buprofezin for 24 months, the NOAEL was 20 ppm equal to 0.9 and 1.1
    mg/kg bw/day for males and females respectively.  The absolute thyroid
    weight and incidence of hypertrophy and hyperplasia of the epithelial
    cells in thyroid increased at 200 ppm and above.  The incidence of
    hepatic hyperplastic nodules was slightly increased in rats at 2000
    ppm.  The Meeting concluded that there was no convincing evidence of
    carcinogenicity in rodents.

         After reviewing the available  in vitro and  in vivo
    genotoxicity assays, the Meeting concluded that there was no evidence
    of genotoxicity.

         An ADI, which was based on the NOAEL in the 2-year study in rats
    using a safety factor of 100, was allocated.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    20 ppm equal to 1.82 mg/kg bw/day
         Rat:      20 ppm equal to 0.9 mg/kg bw/day
         Dog:      2 mg/kg bw/day

    Estimate of acceptable daily intake for humans

         0-0.01 mg/kg bw

    Studies which will provide information valuable in the
    continued evaluation of the compound

         Observations in humans.

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    24-month toxicity study on ST-29285 (Buprofezin) in rats. Unpublished
    report No. ML-185 from preclinical Research Laboratories, Central
    Institute for Experimental Animals, Kanagawa, Japan. Submitted to WHO
    by Nihon Nohyaku Co., Ltd., Tokyo, Japan.

    Yoshida, A. (1983) (received in 1990). NNI-750 (Buprofezin): 24-month
    oral toxicity and oncogenicity study in mice. Unpublished report
    T-1019 from The Institute of Environmental Toxicology, Tokyo, Japan.
    Submitted to WHO by Nihon Nohyaku Co., Ltd., Tokyo, Japan.


    See Also:
       Toxicological Abbreviations