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    TEBUFENOZIDE

    First draft prepared by
    D. Grant & S. Ma
    Pesticide Evaluation Division, Health Evaluation Division,
    Health Canada, Tunney's Pasture, Ottawa, Ontario, Canada

    Explanation
    Evaluation for acceptable daily intake
       Biochemical aspects
          Absorption, distribution, and excretion
          Biotransformation
       Toxicological studies
          Acute toxicity
          Short-term toxicity
          Long-term toxicity and carcinogenicity
          Reproductive toxicity
          Developmental toxicity
          Genotoxicity
          Special studies
             Dermal and ocular irritation and dermal sensitization
             Neurotoxicity
             Studies on metabolites
    Comments
    Toxicological evaluation
    References

    Explanation

         Tebufenozide, 4-ethylbenzoic acid- N'-tert-butyl- N'-(3,5-di-
    methylbenzoyl)hydrazide, is a fat-soluble insecticide used to control
    Lepidoptera pests in fruits, vegetables, and other crops. It has a
    novel mode of action, in that it mimics the action of the insect
    moulting hormone, ecdysome. Lepidoptera larvae cease to feed within
    hours of exposure to tebufenozide and then undergo a lethal
    unsuccessful moult.

         Tebufenozide was evaluated for the first time by the present
    Meeting.

    Evaluation for acceptable daily intake

    1.  Biochemical aspects

    (a)  Absorption, distribution, and excretion

         Three groups of four male and four female Crl:CD BR rats were
    fasted overnight and then given a single dose by gavage of 250 mg/kg
    bw of either [14C- tert-butyl]tebufenozide, [14C-A-ring]-tebufenozide,
    or [14C-B-ring]tebufenozide. The profile of excretion of radiolabel
    by males and females was similar. Absorption and excretion of 14C
    label were rapid, with > 70% of the administered dose eliminated
    within 48 h. The mean total excreted over seven days was > 82%. Faeces
    was the major route of excretion, representing at least 98% of the
    total radiolabel excreted; only minor amounts (1-2% of dose) were
    excreted in the urine and trace amounts (< 0.05% of dose) in expired
    air as 14C-carbon dioxide or volatile organic compounds. Little
    radiolabel was retained in organs or tissues by seven days after
    dosing: < 0.1% of the [14C- tert-butyl]-labelled material, < 0.03%
    [14C-A-ring]tebufenozide, and < 0.01% [14C-B-ring]-tebufenozide.
    The highest tissue concentrations were found in the liver, blood,
    spleen, and fat (0.5-1.3 g/g 14C-tebufenozide equivalents) of
    animals given [14C- tert-butyl]- labelled material and in the
    fat (< 1 g/g) of animals given [14C-A-ring]-tebufenozide. The
    concentrations of radiolabel in the tissues of animals given
    [14C-B-ring]tebufenozide were near or below the limit of detection
    (0.4 ppm) (LeVan, 1991).

         Four male and four female Crl:CD BR rats received a bile-duct
    cannula, were fasted overnight, and were then given a single dose of
    3 mg [14C- tert-butyl]tebufenozide/kg bw by gavage. The absorption
    and elimination of radiolabel were followed up to 72 h. No significant
    difference in the excretion profile was seen between males and females.
    The absorption and excretion of radiolabel were rapid, and about 100%
    of the administered dose was recovered in excreta within 24 h. Most of
    the radiolabel (67-70%) was unabsorbed and was eliminated directly in
    the faeces. Systemic absorption was calculated to be 35-39% of the
    total administered dose; 30-34% was excreted in the bile and approx. 5%
    in the urine. Tissue retention of radiolabel was very low, with a mean
    of 0.3-0.4% remaining in the carcass 72 h after dosing (Struble &
    Hazelton, 1992a).

         Groups of three to six male and female Crl:CD BR Sprague-Dawley
    rats were given a single dose of either [14C- tert-butyl]-tebufenozide,
    [14C-A-ring]tebufenozide, or [14C-B-ring]-tebufenozide by gavage
    at nominal doses of 3 or 250 mg/kg bw. One group of animals was fed
    a diet containing 30 ppm nonradioactive tebufenozide for two weeks
    before receiving a single oral dose of 3 mg/kg bw [14C- tert-butyl]-
    tebufenozide. The absorption and excretion of the radiolabel were
    very rapid. The excretion profiles were similar, regardless of the 

    position of the 14C label, the dose, the sex of the rat, or whether
    the animals were pretreated with tebufenozide. A mean total of 87-104%
    of the administered dose was excreted within 48 h of dosing, primarily
    via the faeces, which accounted for > 90% of the radiolabel excreted;
    only minor amounts (< 1-8% of the dose) were excreted in the urine. 
    Trace amounts of radiolabel (< 0.1-0.4% of the dose) were recovered
    as carbon dioxide and volatile organic compounds in the expired air
    of rats dosed with [14C- tert-butyl]tebufenozide but not from
    rats dosed with the A-ring or B-ring label. Maximal levels of
    radiolabel were measured in the blood 0.5-12 h after dosing. Clearance
    of the A-ring and B-ring labels from the circulation was very rapid,
    such that no 14C was detected in blood 24 h after dosing. In
    contrast, disappearance of radiolabel from the blood of animals given
    the  tert-butyl label was relatively slow, low levels being detected
    10 days after dosing. The peak concentration of radiolabel in blood
    was not proportional to the dose administered, suggesting that the
    pharmacokinetics of 14C-tebufenozide are not linear between the low
    (3 mg/kg bw) and high (250 mg/kg bw) doses. Tissue retention of
    radiolabel was very low; by 168 h after treatment, the mean totals of
    the administered dose retained were < 1, < 0.2, and < 0.01% of the
     tert-butyl, A-ring, and B-ring labels, respectively, at 3 mg/kg bw
    and < 0.01% of any of the three labels at 250 mg/kg bw. The highest
    concentrations of radiolabel were consistently found in the liver,
    fat, and kidneys; all other tissues contained < 0.01 ppm or
    undetectable levels, regardless of the position of the label, the
    dose, or the sex of the rat. The distribution in the tissues was
    consistent with the pharmacokinetic data and indicated that the 14C
    associated with the A-ring and B-ring labels was cleared more rapidly
    from the tissues than that associated with the  tert-butyl label
    (Struble & Hazelton, 1992b).

    (b)  Biotransformation

         Groups of Crl:CD BR Sprague-Dawley rats were given [14C- 
     tert-butyl]-, [14C-A-ring]-, or [14C-B-ring]tebufenozide by gavage
    at a dose of 3 mg/kg bw or [14C- tert-butyl]- or [14C-B-ring]-
    tebufenozide at 250 mg/kg bw. Faeces and urine were collected from
    five rats of each sex per group and analysed for tebufenozide
    metabolites. Parent tebufenozide was the major component present in the
    faeces, accounting for > 90% of the administered dose at the high dose
    and > 35% at the low dose. Eleven metabolites were identified in the
    faeces of animals at the high dose and 14 in faeces from those at the
    low dose; 10 of the metabolites were common to the two groups. No
    qualitative difference in metabolite profile was seen with the
    differently labelled versions of tebufenozide. No parent tebufenozide
    was found in the urine, but many of the metabolites were the same as
    those found in the faeces. An additional two or three unknown
    metabolites, representing 3-3.5% of the total dose, were found in
    acidified fractions of urine from animals given A- or B-ring labelled
    material. These were probably partially fragmented metabolites of
    
    tebufenozide in which the  tert-butyl group had been metabolically
    cleaved. The faecal and urinary analyses thus indicate a total of 15
    metabolites (all except one present at < 1% of the dose) in excreta
    from animals at the high dose and 14 metabolites (two present at > 10%
    and nine at > 1% of the dose) in excreta from animals at the low dose.
    The extent of metabolism of tebufenozide was highly dependent on the
    amount of test material administered. Thus, only about 4% of the high
    dose was metabolized, producing about 10 mg/kg bw of metabolites,
    whereas about 46% of the low dose was metabolized, producing about
    1.4 mg/kg bw of metabolites. The major route of metabolism of
    tebufenozide appeared to be oxidation of benzylic carbons (A or B
    ring) to provide a number of oxidized metabolites with various
    combinations of oxidation states at the 3-carbon centres. One
    exception was RH-2703 (see Figure 1), which was produced by oxidation
    of the non-benzylic terminal carbon on the A-ring ethyl group. A
    metabolic pathway for tebufenozide in rats was proposed (Figure 1)
    (Hawkins  et al., 1992).

         The metabolism of tebufenozide was studied in Crl:CD BR
    Sprague-Dawley rats given a single dose of 3 mg/kg bw of [14C- tert-
    butyl]tebufenozide by gavage. One group was fed 30 ppm of non-
    radioactive tebufenozide in the diet for two weeks before receiving
    the radiolabelled material. Faeces and urine from five males and five
    females were collected and analysed for tebufenozide metabolites. The
    parent tebufenozide was a major component of faeces, accounting for
    26-39% of the administered radiolabel, and 13 metabolites were
    identified. Significant differences between males and females in the
    levels of several metabolites were noted: the major faecal metabolites
    were RH-0282, RH-120898, and RH-0126 in animals of each sex and
    RH-122777 in females only. No parent tebufenozide was found in the
    urine, but many of the 13 metabolites found were the same as those in
    faeces. No significant qualitative differences in the metabolism of
    14C-tebufenozide were found between rats pretreated with 30 ppm
    dietary tebufenozide and those receiving the single 14C-radiolabelled
    dose without pretreatment. Quantitatively, slightly less parent
    tebufenozide was found in the excreta of pulse-dosed than those of
    single-dosed animals, suggesting that slightly more tebufenozide
    metabolism occurred in the former, which also had generally higher
    levels of the more highly oxidized metabolites in their excreta
    (Hawkins  et al., 1993).

    FIGURE 8

         Groups of Crl:CD BR Sprague-Dawley rats received a bile-duct
    cannula and then a single oral dose of 3 mg/kg bw [14C- tert-butyl]-
    tebufenozide. Bile samples collected from one male and one female rat
    during 0-6 h after treatment, representing about 70% of total biliary
    excretion of radiolabel over 72 h, were analysed for tebufenozide
    metabolites. No parent compound was found; 13 biliary metabolites were
    identified, and five unknown metabolites were isolated. In general,
    the biliary metabolites were identical to those in the faeces and
    urine, but three new metabolites were observed: [A-ring]-ketone-
    [B-ring]-diol, RH-122652, and RH-2652. The last two were also
    identified by mass spectroscopy in the faeces but at levels too low
    for quantification. The unknown metabolites in bile appeared to be
    high-molecular-mass amino-acid conjugates of acidic tebufenozide
    metabolites. It was postulated that these conjugates are metabolized
    in rats before excretion in order to recover the amino acids; hence,
    their absence in faeces (Hawkins & Hazelton, 1993).

    2.  Toxicological studies

    (a)  Acute toxicity

         The results of studies of the acute toxicity of tebufenozide are
    summarized in Table 1. Tebufenozide was of low toxicity to mice and
    rats when given orally, dermally, or by inhalation. No deaths or
    clinical signs of systemic toxicity were observed at doses < 5.0 g/kg
    bw. Dermal administration resulted only in transient, mild local
    erythema at the site of application. After inhalation, accumulation
    of red-brown material was seen around the nose, mouth, and eyes,
    sometimes with a purulent anogenital discharge which lasted for one
    to three days.

    (b)  Short-term toxicity

    Mice

         Six groups of eight male albino Crl:CD-1 ICR BR mice were fed
    diets containing technical-grade tebufenozide (purity, 94%) to provide
    doses of 0, 60, 200, 600, 2000, or 6000 ppm, equal to 0, 12, 39, 97,
    350, or 1100 mg/kg bw per day, for two weeks. At the highest dose, the
    absolute and relative liver weights were significantly increased,
    but, in the absence of histopathological data, the toxicological
    significance of this change could not be fully evaluated. The NOAEL
    was 600 ppm, equal to 97 mg/kg bw per day, on the basis of the
    increased relative liver weights (Kyle, 1992).

        Table 1.  Acute toxicity of tebufenozide in experimental animals

                                                                                                         

    Species          Sex             Route          LD50 (mg/kg bw)                  Reference
                                                   or LC50 (mg/litre)
                                                                                                         

    Mouse        Male, female      Oral                  > 5000            Morrison & Hamilton (1991a)
    Rat          Male, female      Oral                  > 5000            Morrison & Hamilton (1991b)
    Rat          Male, female      Dermal                > 5000            Morrison & Hamilton (1991c)
    Rat          Male              Inhalation            > 4.3             Ulrich (1992)
                 Female                                  > 4.5
                                                                                                         
             Groups of 10 male and 10 female Crl:CD-1 ICR BR VAF/Plus mice
    were fed diets containing technical-grade tebufenozide (purity, 98.6%)
    providing levels of 0, 20, 200, 2000, or 20 000 ppm, equal to 0, 3.4,
    35, 340, and 3300 mg/kg bw per day for males and 0, 4.3, 45, 430, and
    4200 mg/kg bw per day for females, for 13 weeks. At 200 ppm, slightly
    reduced mean body-weight gain (but not overall body weight) was seen
    in males and a marginally higher incidence of increased extramedullary
    haematopoiesis in the spleen and pigment accumulation in kidney
    tubules (with no concomitant changes in haematological parameters) in
    females; these changes were considered not to be toxicologically
    significant. At 2000 and 20 000 ppm, significant haemolytic changes
    and a reduced mean myeloid:erythroid ratio in bone marrow were seen,
    with dose-related increases in the absolute and relative (to body
    and to brain) weights of the spleen and liver. Histopathological
    examination revealed an increased incidence and/or severity of pigment
    deposition in the liver, spleen, and kidney tubules and increased
    extramedullary haematopoiesis in the spleen. The pigment was
    characterized as bile in the liver and haemosiderin in the liver,
    spleen and kidney. The primary target of tebufenozide was the
    erythrocyte, causing increased erythrocyte turnover and compensatory
    responses from the haematopoietic tissues. The NOAEL was 200 ppm,
    equal to 35 mg/kg bw per day (Osheroff, 1991a).

    Rat

         Groups of six male and six female Crl:CD BR rats were given
    technical-grade tebufenozide (purity, 94%) in the diet to provide
    levels of 0, 50, 250, 1000, 2500, or 10 000 ppm, equal to 0, 3.8, 19,
    71, 180, and 700 mg/kg bw per day for males and 0, 4.5, 21, 85, 210
    and 780 mg/kg bw per day for females, for two weeks. The relative
    weight of the liver was increased in males and the absolute and
    relative weights in females at 1000 ppm; however, in the absence of
    histopathological data, the toxicological significance of these
    changes could not be fully evaluated. At 10 000 ppm, slight reductions
    in body-weight gain, food consumption, and erythrocyte parameters were
    seen, which were within the normal range of biological variations and
    were considered to be of minimal toxicological significance. At this
    dose, increased absolute and relative spleen weights were observed in
    males and females; however, in the absence of histopathological data,
    the significance of these changes could not be evaluated. The NOAEL
    was 250 ppm, equal to 19 mg/kg bw per day, on the basis of the changes
    in liver weight (Kyle & Quinn, 1992).

         In a range-finding study, groups of 10 male and 10 female Crl:CD
    BR Sprague-Dawley rats were given diets containing technical-grade
    tebufenozide (purity, 96.4%) to provide levels of 0 or 20 000 ppm,
    equal to 0 and 1500 mg/kg bw per day in males and 0 and 1600 mg/kg bw
    per day in females, for four weeks. Decreases in body weight (< 9%),
    body-weight gain, and food consumption (< 12%) were observed, but the
    mean efficiency of food use was not affected, suggesting reduced

    palatability of the 20 000-ppm test diet. Slight reductions in
    erythrocyte count, haemoglobin, and haematocrit were seen. The
    absolute and relative liver weights of animals of each sex, the
    absolute and relative spleen weights of males, and the relative kidney
    weights of females were higher in the treated rats, but, in the
    absence of histopathological data, the toxicological significance of
    these changes could not be fully assessed. It was concluded that the
    high dietary level of 20 000 ppm could be used in studies of short-
    term toxicity in rats (Osheroff, 1991b).

         Groups of 10 male and 10 female Crl:CD BR rats were fed diets
    containing technical-grade tebufenozide (purity, 96.4 or 98.6%) in the
    diet to provide levels of 0, 20, 200, 2000, or 20 000 ppm, equal to 0,
    1.3, 13, 130, and 1300 mg/kg bw per day for males and 0, 1.6, 16, 160,
    and 1600 mg/kg bw per day for females, for 13 weeks. The dose of
    2000 ppm induced significant decreases in overall body-weight gain and
    mean food consumption during the first four weeks of dosing and an
    increase in the relative (to brain) weight of the liver in females.
    Slight haemolytic anaemia, increased bone-marrow erythropoiesis
    (decreased mean myeloid:erythroid ratio), and increased deposition of
    pigment in the spleen were observed. At the highest dose, additional
    treatment-related effects included overt haemolytic changes, slightly
    elevated absolute and relative (to brain) spleen weights in animals of
    each sex, elevated absolute liver weight in females, and tubular
    nephrosis of the kidney in four males. The NOAEL was 200 ppm, equal to
    13 mg/kg bw per day (Osheroff, 1991c).

         Groups of six male and six female Crl:CD BR rats received
    applications of technical-grade tebufenozide (purity, 97.2%) moistened
    with 0.9% saline (1:6 w/v) at a dose of 1000 mg/kg bw per day on the
    shaved, intact skin of the back under semi-occlusive bandages for
    6 h per day, five days per week for four weeks (a total of 21
    applications). No signs of treatment-related systemic toxicity or
    dermal irritation were observed. The NOAEL was thus 1000 mg/kg bw per
    day (Morrison  et al., 1993).

    Dogs

         Five groups of four male beagle dogs received diets containing
    technical-grade tebufenozide (purity, 96.8%) at 0, 150, 600, 2400,
    or 9600 ppm, equal to 0, 5, 19, 77, and 290 mg/kg bw per day, for
    two weeks. A significant increase in the mean spleen weight was
    seen in animals at 600 ppm. At 9600 ppm, mild haemolytic anaemia
    (significantly reduced erythrocyte count, haemoglobin, and
    haematocrit) was observed. The NOAEL was 150 ppm, equal to 5 mg/kg bw
    per day (Kehoe, 1990).

         Two groups of four male beagle dogs were fed diets containing
    technical-grade tebufenozide (purity, 97.5%) at 0 or 1500 ppm,
    equal to 42 mg/kg bw per day, for six weeks. All animals were then
    maintained on the basal diet for a four-week recovery period, after
    which the study was terminated. Haematological examinations were
    performed on all dogs before treatment and at 6, 8, and 10 weeks.
    Administration of 1500 ppm resulted in mild regenerative anaemia, but
    total recovery had occurred four weeks after cessation of treatment
    (Yoshida, 1992).

         Groups of four male and four female beagle dogs received diets
    containing technical-grade tebufenozide (purity, 96.1%) at 0, 50,
    500, or 5000 ppm, equal to 0, 2.1, 20, and 200 mg/kg bw per day for
    males and 0, 2, 21, and 200 mg/kg bw per day for females, for 90
    days. Animals of each sex at 500 ppm had an increased incidence of
    Heinz bodies, and females at this dose had an elevated mean total
    bilirubin level and increased absolute and relative spleen weights.
    Histopathological examination revealed an increased incidence of
    pigment deposition (haemosiderin) in the Kupffer cells of the liver
    and increased haematopoiesis and sinusoidal engorgement of the spleen.
    At the highest dose, significant haemolytic changes and increased
    bone-marrow erythropoiesis (reduced mean myeloid:erythroid ratio) were
    seen at weeks 6 and 13 of treatment. The mean total plasma bilirubin
    level was elevated in animals of each sex, and bilirubin was present
    in the urine of three males. Increased absolute and relative spleen
    weights and slightly higher relative liver weights were observed.
    Increased incidences of pigment deposition (haemosiderin) and the
    presence of erythrocytes in some Kupffer cells of the liver suggested
    active erythrophagocytosis. Increased splenic haematopoiesis, splenic
    sinusoidal engorgement, and bone-marrow hyperplasia were also noted.
    The primary target of tebufenozide in the dog was the erythrocytes,
    leading to mild haemolytic anaemia and compensatory responses from the
    haematopoietic tissues. The NOAEL was 50 ppm, equal to 2 mg/kg bw per
    day (Clay, 1992).

         Groups of four male and four female beagle dogs were fed diets
    containing technical-grade tebufenozide (purity, 97.5%) providing
    dietary levels of 0, 15, 50, 250, or 1500 ppm, equal to 0, 0.6, 1.8,
    8.7, or 53 mg/kg bw per day for males and 0, 0.6, 1.9, 8.9, and
    56 mg/kg bw per day for females, for 52 weeks. In animals at 250 ppm,
    slight but consistent haemolytic changes and a slightly elevated total
    plasma bilirubin level were seen, the latter especially in females,
    over the 52-week period. The mean absolute and relative spleen weights
    of females and the mean relative liver weight of males were increased,
    and an increased incidence of pigment deposition in the Kupffer
    cells of the liver, increased splenic haematopoiesis and sinusoidal
    engorgement, and bone-marrow hyperplasia were also observed. Similar
    treatment-related effects of increased magnitude and severity were

    observed at the highest dose. The primary target of tebufenozide was
    thus erythrocytes, leading to mild peripheral haemolytic anaemia and
    compensatory responses from the haematopoietic tissues. The NOAEL was
    50 ppm, equal to 1.8 mg/kg bw per day (Richards, 1992).

    (c)  Long-term toxicity and carcinogenicity

    Mice

         Groups of 50 male and 50 female Crl:CD-1(ICR)BR mice received
    diets containing technical-grade tebufenozide (purity, 96.1%) at 0, 5,
    50, 500, or 1000 ppm, equal to 0, 0.8, 7.8, 78, and 160 mg/kg bw per
    day for males and 0, 0.9, 9.4, 94, and 190 mg/kg bw per day for
    females, for 18 months. Each group included a satellite group of 10
    mice of each sex that were killed at interim sacrifice after 52 weeks
    of treatment. In animals at 500 ppm, a slight reduction in the
    survival rate of males and increased pigment deposition in the spleens
    of males and females were observed at both interim and terminal
    sacrifices. At the highest dose, the survival rates of both males
    and females were reduced, and signs of mild haemolytic anaemia (a
    small but significant increase in the blood level of methaemoglobin
    and increased incidences of polychromasia and echinocytosis in
    erythrocytes) and further increases in splenic pigment deposition were
    observed at interim and/or terminal sacrifice. At terminal sacrifice,
    males had increased relative spleen weights, and females had an
    increased incidence of extramedullary haematopoiesis in the spleen.
    There was no evidence of an oncogenic effect at any dose. The NOAEL
    for general toxicity was 50 ppm, equal to 7.8 mg/kg bw per day
    (Trotter, 1992a).

    Rats

         Groups of 60 male and 60 female Crl:CD BR rats received diets
    containing technical-grade tebufenozide (purity, 96.1%) providing
    levels of 0, 10, 100, 1000, or 2000 ppm, equal to 0, 0.5, 4.8, 48, and
    97 mg/kg bw per day for males and 0, 0.6, 6.1, 61, and 120 mg/kg bw
    per day for females, for two years. Each group included a satellite
    group of 10 rats of each sex that were killed at interim sacrifice
    during week 53; two sentinel groups of five rats of each sex per group
    were maintained to screen general health before and at the end of the
    treatment period. Animals at 1000 or 2000 ppm showed significant
    decreases in mean body weight and body-weight gain, the latter more
    pronounced in females, and females had a reduced mean food consumption
    throughout the study. Signs of mild haemolytic anaemia were seen only
    during the first 52 weeks of treatment, suggesting that the effects
    on the haematopoietic system were transient and reversible. Slight
    increases in the incidence and/or severity of pigment deposition
    (haemosiderin) were seen in the spleens of animals of each sex at
    interim and/or terminal sacrifices, suggesting active splenic
    erythrophagocytosis. In addition, females at 1000 and 2000 ppm had an

    increased frequency of swelling of body areas (principally the mammary
    gland regions) during the first 70 weeks of treatment; however, in the
    absence of any supporting histopathological findings in the mammary
    gland tissue or skin, the toxicological significance of these
    transient swellings could not be ascertained. No treatment-related
    neoplastic lesions were noted in any tissue or organ of any treated
    rat at any dose. The NOAEL for systemic toxicity was 100 ppm, equal to
    4.8 mg/kg bw per day (Trutter, 1992b).

    (d)  Reproductive toxicity

    Rats

         In a two-generation study, with one litter per generation, groups
    of 25 male and 25 female weanling Crl:CD BR rats were fed diets
    containing technical-grade tebufenozide (purity, 97.5%) providing
    dietary levels of 0, 10, 150, or 2000 ppm, equal to 0, 0.8, 12, and
    150 mg/kg bw per day for males and 0, 0.9, 13, and 170 mg/kg bw per
    day for females. The diets were fed for 70 (F0) or 105 days (F1)
    before mating. No treatment-related effects were observed in either
    generation at the low dose. At 150 ppm, an increased severity of
    pigment deposition in the spleen of F0 and F1 females was reported.
    At the highest dose, the body weight and feed consumption of F0 and
    F1 males were decreased at some intervals before mating. Increased
    splenic pigment deposition and extramedullary haematopoiesis were seen
    in parental animals of each sex in both generations. The mean number
    of implantation sites in F1 females (not measured in F0) was
    decreased and the length of gestation in F1 (but not F0) dams
    increased. There was also a small increase in the number of pregnant
    females in both generations that had total resorptions and in the
    number of F1 females that died during delivery. The NOAEL was 10 ppm,
    equal to 0.8 mg/kg bw per day, for general toxicity and 150 ppm, equal
    to 12 mg/kg bw per day, for reproductive toxicity (Danberry  et al.,
    1993).

         In a similar study, groups of 24 male and 24 female weanling
    Crj:CD(SD) rats were given diets containing technical-grade
    tebufenozide (purity, 97.2%) providing levels of 0, 25, 200, or
    2000 ppm, equal to 0, 1.6, 13, and 130 mg/kg bw per day for males and
    0, 1.8, 15, and 140 mg/kg bw per day for females, for 10 weeks before
    mating of the F0 and F1 parents to produce the respective F1 and F2 
    offspring. The study was terminated after weaning of the F2 litters.
    An increased incidence of splenic lesions, seen as blackish changes
    and/or congestion of the spleen, increased splenic extramedullary
    haematopoiesis, and haemosiderin-laden cells, occurred in F0 and F1
    parental animals at 200 and 2000 ppm. At 2000 ppm, slight decreases in
    body-weight gain were seen in animals of each sex, and decreases in
    uterine and ovarian weights were reported; the changes were small and
    were considered not to be toxicologically significant. A significant
    reduction in mean body-weight gain was seen in F1 and F2 pups at 

    2000 ppm between lactation days 14 and 21. The study revealed no
    adverse effects on the reproductive ability of male or female rats.
    The NOAEL was 25 ppm, equal to 1.6 mg/kg bw per day, for systemic
    toxicity and 200 ppm, equal to 13 mg/kg bw per day, for reproductive
    toxicity (Aso, 1995).

         In both of the above studies, a consistent increase in the
    incidence of gross and histopathological findings in the spleen,
    including congestion, pigment, and extramedullary haematopoiesis, was
    seen in F0 and F1 parental animals. Although tebufenozide at the
    doses tested had no effect on the reproductive ability of male or
    female rats, the minor reproductive effects observed at 2000 ppm
    on parental females in the first study and on lactating pups in
    the second study could not be discounted. The overall NOAEL for
    reproductive toxicity was thus 200 ppm, equal to 13 mg/kg bw per day.

    (e)  Developmental toxicity

    Rats

         In a range-finding study, groups of nine mated female Crl:CD BR
    rats were given technical-grade tebufenozide (purity, 96.8%) by gavage
    at doses of 0 (vehicle control), 25, 75, 200, or 400 mg/kg bw per day
    on days 6-15 of gestation. On day 20, all surviving dams were killed,
    and their fetuses were removed from the uterus and necropsied.
    No maternal, embryo, or fetal toxicity and no external gross
    malformations or anomalies in the fetuses were seen at any dose. The
    NOAEL for maternal, embryonic, and fetal toxicity and teratogenicity
    was thus 400 mg/kg bw per day, the highest dose tested. In a
    supplementary range-finding study, groups of six non-pregnant female
    Crl:CD BR rats were given technical-grade tebufenozide (purity, 96.8%)
    by gavage at doses of 0, 400, or 1000 mg/kg bw per day for 10 days. At
    1000 mg/kg bw per day, a slight increase in liver weight was observed;
    however, in the absence of histopathological data, the toxicological
    significance of this finding could not be fully evaluated. On the
    basis of the very limited data provided, the NOAEL was 400 mg/kg bw
    per day (Solomon & Romanello, 1992).

         In the main study, groups of 25 mated Crl:CD BR VAF/Plus
    Sprague-Dawley rats were given technical-grade tebufenozide (purity,
    96.1%) by gavage at doses of 0, 50, 250, or 1000 mg/kg bw per day on
    days 6-15 of presumed gestation (day 0 taken as the day spermatozoa
    were detected in a vaginal lavage or a copulatory plug was observed
     in situ). On gestation day 20, all surviving dams were killed, and
    their fetuses were removed and necropsied. At 1000 mg/kg bw per day,
    initial slight, transient reductions in mean body-weight gain and food
    consumption were seen during dosing, but the mean values over the
    study were not affected; the changes were considered not to be
    toxicologically significant. All of the fetuses showed normal
    development, and no signs of fetotoxicity and no treatment-related

    malformations were observed at any dose tested. The NOAEL was
    1000 mg/kg bw per day for maternal toxicity and 1000 mg/kg bw per
    day, the highest dose tested, for embryo- and fetotoxicity and
    teratogenicity (Hoberman, 1991).

    Rabbits

         In a range-finding study, groups of six mated female Hra:(NZW)SPF
    rabbits were given technical-grade tebufenozide (purity, 96.4%) by
    gavage at doses of 0, 100, 300, or 1000 mg/kg bw per day on days 7-19
    of presumed gestation (the day of mating confirmed by the presence of
    seminal fluid in the vulva). All surviving does were sacrificed, and
    all fetuses were removed and examined on day 29 of gestation. The
    single death due to an unknown cause among animals at 1000 mg/kg bw
    per day was unlikely to have been due to treatment, as no deaths
    occurred in the main study. No other signs of maternal toxicity or
    treatment-related disturbance of intrauterine development of the
    conceptuses were observed. All fetuses showed normal development, and
    no signs of fetal toxicity or treatment-related malformations were
    seen at any dose. The NOAEL for embryo- and fetotoxicity and
    teratogenicity was 1000 mg/kg bw per day, the highest dose tested
    (Lemen, 1991).

         In the main study, groups of 20 mated female New Zealand white
    rabbits were given technical-grade tebufenozide (purity, 97.5%) by
    gavage at doses of 0, 50, 250, or 1000 mg/kg bw per day on days 7-19
    of presumed gestation (the day of mating confirmed by the presence of
    seminal fluid in the vulva). All surviving does were sacrificed, and
    their fetuses were removed and examined on day 29 of gestation. No
    treatment-related deaths, clinical signs of maternal toxicity, or
    disturbances of intrauterine development of the conceptuses were
    observed at any dose. All of the fetuses showed normal development,
    and no signs of fetotoxicity or treatment-related malformations were
    observed at any dose. The NOAEL for maternal toxicity, embryo- and
    fetotoxicity and teratogenicity was 1000 mg/kg bw per day, the highest
    dose tested (Swenson & Solomon, 1992).

    (f)  Genotoxicity

         A battery of tests for mutagenicity was conducted to assess the
    potential of technical-grade tebufenozide (purity, > 95-97.5%) to
    induce gene mutation, chromosomal aberration, or unscheduled DNA
    synthesis. The results, summarized in Table 2, were all negative.

    (g)  Special studies

    (i)  Dermal and ocular irritation and dermal sensitization

         Technical-grade tebufenozide (purity, 96-97%) was not irritating
    to the skin and was minimally irritating to the eyes of male New
    Zealand white rabbits, according to Draize scale scoring (Krajewski
     et al., 1988a,b; Lutz & Parno, 1993).

        Table 2.  Results of tests for the genotoxicity of technical-grade tebufenozide

                                                                                                                                      

         End-point                Test system               Concentration          Purity        Results            Reference
                                                                                    (%)
                                                                                                                                      

    In vitro

    Reverse mutation            S. typhimurium           0, 50-5000a g/plate       > 95        Negativeb       Black (1986)
                                TA98, TA100,
                                TA1535, TA1537
    Reverse mutation            S. typhimurium           0, 50-5000a g/plate       96.1        Negativeb       Sames & Streelman
                                TA98, TA100,                                                                    (1991)
                                TA1535, TA1537
    Reverse mutation            S. typhimurium           0, 50-5000a g/plate       96.1        Negativeb       Sames & Elia (1993)
                                TA98, TA100,             0, 160-1600a g/plate                  Negativeb
                                TA1535, TA1537
    Reverse mutation            S. typhimurium           0, 50-5000a g/plate       96.1        Negativeb       Sames & Elia (1994)
                                TA98, TA100,             0, 30-300a g/plate                    Negativeb
                                TA1535, TA1537
    Reverse mutation            E. coli WP2 uvr A        0, 200-5000a g/plate      96.1        Negativeb       Watanabe (1992)
    Forward mutation            Chinese hamster          0, 10-60 g/ml             96.4        Negativeb       Thilagar (1990a)
                                ovary cells
                                (hprt locus)
    Chromosomal aberration      Chinese hamster          0, 5-30 g/ml              96.8        Negativeb       Thilagar (1987)
                                ovary cells
    Unscheduled DNA             Rat (SD) primary         0, 10-100a g/ml           96.4        Negative        Thilagar (1990b)
    synthesis                   hepatocytes              0, 10-60 g/ml                         Negative

    In vivo

    Chromosomal aberration      Rat (CD, 5-7 of each     0, 0.5-5.0 g/kg bw         97.5        Negative        Gudi (1992)
                                sex per dose) bone       by single gavage
                                marrow
                                                                                                                                      

    a    Precipitation observed in all cultures
    b    Conducted with and without exogenous metabolic activation
             Technical-grade tebufenozide (purity, 96%) did not sensitize the
    skin of guinea-pigs assessed in the maximization test (males) and the
    Buehler test (females) (Matsumoto, 1989; Glaza, 1993).

    (ii)  Neurotoxicity

         Groups of 10 male and 10 female Crl:CD R BR rats were given
    single doses of technical-grade tebufenozide (purity, 96.1%) in
    0.5% w/v aqueous methylcellulose by gavage at 0, 500, 1000, or
    2000 mg/kg bw. All rats were subjected to functional observational
    battery testing and motor activity assessment before treatment and
    1-3 h and 7 and 14 days after dosing, and a detailed neuropathological
    examination was carried out at the end of the 14-day observation
    period. No remarkable treatment-related neurological changes were
    found at any dose. Treatment-related responses were elicited in
    similar acute neurotoxicity studies conducted at the same testing
    laboratory with substances known to affect functional observational
    battery and motor activity testing, thus validating the competence of
    the laboratory in this type of testing. The NOAEL for the neurotoxic
    and neuropathological effects of tebufenozide was thus 2000 mg/kg bw,
    the highest dose tested (Swenson  et al., 1994).

    (iii)  Studies of metabolites

         Five metabolites of tebufenozide were tested for acute toxicity
    in Crj: CD-1 or Crl:CD-1 BR ICR mice. Metabolites RH-111788, RH-96595,
    RH-120970, RH-089886, and RH-112651 (see Figure 1) given orally
    induced no deaths and no clinical signs of systemic toxicity at doses
    up to 5000 mg/kg bw. The LD50 values for these metabolites in male
    and female mice was thus > 5000 mg/kg bw (Hazelton & Quinn, 1993).

         Four tebufenozide metabolites, RH-111788, RH-96595, RH-120970,
    and RH-089886, were tested for their potential to induce reverse
    mutation in  Salmonella typhimurium strains TA98, TA100, TA1535, and
    TA1537 and in  Escherichia coli strain WP2  uvr A at concentrations up 
    to the limit of solubility (1250-2500 g/plate), with and without
    exogenous metabolic activation. The results, summarized in Table 3,
    were negative (Hazelton & Quinn, 1993).

    Table 3.  Results of tests for the genotoxicity of metabolites
              of tebufenozide

                                                                      

    Metabolite                         Concentration       Result
                                        (g/plate)
                                                                      

    RH-89886 (in rats, rice)           0, 313-5000a       Negative
    RH-111788 (in rats, rice)          0, 313-5000a       Negative
    RH-96595 (in rats, rice, soil)     0, 313-5000a       Negative
    RH-120970 (in rats, rice)          0, 313-5000a       Negative
                                                                      

    Potential for induction of reverse mutation in vitro in S.
    typhimurium TA98, TA100, TA1535, and TA1537 and in E. coli
    WP2 uvr A, with and without exogenous metabolic activation by
    a microsomal fraction from rat liver
    a    Precipitation observed on all plates

    Comments

         Oral administration to rats of single doses of 3 or 250 mg/kg
    bw of 14C-labelled tebufenozide resulted in rapid absorption and
    excretion in urine and faeces, only trace amounts of 14C being
    recovered in expired air. The excretion profiles were similar,
    regardless of the position of the 14C label, the dose, the sex, or
    whether the rats had been pretreated with 30 ppm of unlabelled
    tebufenozide in the diet for two weeks. A mean total of 87-104% of the
    administered radiolabel was eliminated within 48 h, primarily via the
    faeces, which accounted for 90% of the 14C that was excreted; only
    minor amounts (1-8%) were excreted in urine and trace amounts
    (0.1-0.4%) in expired air. In animals at 3 mg/kg bw, absorption
    accounted for 35-39 % of the administered radiolabel; 30-34% was
    excreted in the bile and about 5% in the urine. In rats at 250 mg/kg
    bw, only about 4% of the administered dose was absorbed and
    metabolized. The highest levels of 14C in the blood were measured
    0.5-12 h after dosing, and clearance of the radiolabel from the
    circulation was rapid. Tissue retention of 14C was low, suggesting
    that there is little or no bioaccumulation of tebufenozide in the
    body.

         Most of the 14C excreted in the faeces was in the form of
    unabsorbed (parent) tebufenozide, which accounted for about 60 and 90%
    of an administered dose of 3 and 250 mg/kg bw per day, respectively;
    no unchanged tebufenozide was detected in the urine. The absorbed
    14C-tebufenozide was extensively metabolized in rats. There were no
    significant qualitative differences in the metabolic profiles
    associated with the position of the 14C label, the dose, sex, or
    whether rats were pretreated with unlabelled tebufenozide. In general,
    the 13-15 metabolites identified in the urine, faeces, and bile were
    identical. The main route of metabolism of tebufenozide appeared to be
    oxidation of benzylic carbons (A- or B-ring), resulting in a number of
    metabolites with various combinations of oxidation state at the three
    oxidized carbon centres and one metabolite produced by oxidation of a
    nonbenzylic, terminal carbon on the A-ring ethyl group.

         Tebufenozide was of low acute toxicity after administration to
    mice orally and to rats by the oral, dermal, or inhalation route. The
    oral LD50 in mice and rats was > 5000 mg/kg bw; the dermal LD50 in
    rats was > 5000 mg/kg bw; and the inhalation LC50 in rats was
    > 4.3 mg/litre. The metabolites were also of low acute toxicity to
    mice after oral administration. Tebufenozide was not irritating to
    the skin and was minimally irritating to the eyes of male rabbits;
    it was not a skin sensitizer in guinea-pigs. WHO has not classified
    tebufenozide for acute toxicity.

         Repeated short-term oral administration of tebufenozide to mice
    (2 and 13 weeks), rats (2, 4, and 13 weeks), and dogs (2, 6, 13, and
    52 weeks) resulted primarily in haematotoxic effects (regenerative
    haemolytic anaemia and compensatory responses from the haematopoietic
    tissues). The NOAEL for these effects was 200 ppm, equal to 35 mg/kg
    bw per day, in mice in a 13-week study (0, 20, 200, 2000, and 20 000
    ppm tested); 200 ppm, equal to 13.1 mg/kg bw per day, in rats in a
    13-week study (0, 20, 200, 2000, and 20 000 ppm tested); 50 ppm, equal
    to 2 mg/kg bw per day, in dogs in a 13-week study (0, 50, 500, and
    5000 ppm tested); and 50 ppm, equal to 1.8 mg/kg bw per day, in a
    one-year study in dogs (0, 15, 50, 250, and 1500 ppm tested). Repeated
    dermal applications of tebufenozide to rats for four weeks caused
    no systemic toxicity at doses < 1000 mg/kg bw per day. The dog
    appeared to be the most sensitive species for both short-term and
    long-term toxicity.

         In an 18-month study of toxicity and carcinogenicity in mice
    given tebufenozide in the diet at concentrations of 0, 5, 50, 500,
    or 1000 ppm, the NOAEL for systemic toxicity was 50 ppm, equal to
    7.8 mg/kg bw per day, on the basis of a slightly reduced survival
    rate and mild regenerative haemolytic anaemia at higher doses. In
    a two-year study of toxicity and carcinogenicity in rats given
    tebufenozide in the diet at 0, 10, 100, 1000, or 2000 ppm, the NOAEL
    was 100 ppm, equal to 4.8 mg/kg bw per day, on the basis of decreased
    body weight and food consumption and mild regenerative haemolytic
    anaemia at higher doses. Tebufenozide was not carcinogenic to mice or
    rats under the conditions of the studies.

         Tebufenozide and its metabolites have been adequately tested for
    genotoxicity in a range of assays both  in vitro and  in vivo. The
    Meeting concluded that neither tebufenozide nor its metabolites are
    genotoxic.

         In two two-generation studies of reproductive toxicity in rats,
    with one litter per generation, doses of 0, 10, 150, or 2000 ppm and
    0, 25, 200, or 2000 ppm were administered. The NOAEL for systemic
    (parental) toxicity was 25 ppm, equal to 1.6 mg/kg bw per day, on
    the basis of a consistent increase in the incidence of gross and
    histopathological lesions in the spleens (congestion, pigment, and
    extra-medullary haematopoiesis) of F0 and F1 parental animals at
    higher doses (200 and 2000 ppm). The NOAEL for reproductive toxicity
    was 13 mg/kg bw per day, on the basis of minor reproductive effects
    (decreased mean number of implantation sites, prolonged gestation, a
    slightly greater frequency of total resorptions, and a small increase
    in the number of dams that died during delivery) at the high dose of
    2000 ppm in dams in the first study and in lactating pups (decreased
    mean weight gain on lactation days 14 and 21) in the second study.

         In studies of developmental toxicity in rats and rabbits, doses
    of 0, 50, 250, or 1000 mg/kg bw per day were administered. There was
    no evidence of teratogenic potential. The NOAEL for maternal, embryo-,
    and fetotoxicity and teratogenicity was 1000 mg/kg bw per day, the
    highest dose tested, in both species.

         In a study of acute neurotoxicity in rats, no treatment-related
    effects were seen when single doses of 0, 500, 1000, or 2000 mg/kg bw
    were administered. The NOAEL for acute neurotoxicity and neuro-
    pathological effects was 2000 mg/kg bw, the highest dose tested.

         In summary, exposure to tebufenozide by the oral route results
    primarily in haematotoxicity. The main target of its action is the
    peripheral haematopoietic system; the pivotal toxicological end-point
    of concern, which is seen consistently across all species tested, is
    mild regenerative haemolytic anaemia with compensatory responses from
    the haematopoietic tissues.

         An ADI of 0-0.02 mg/kg bw was established for tebufenozide on the
    basis of the NOAELs for haematotoxicity of 1.8 mg/kg bw per day in the
    one-year study in dogs and 1.6 mg/kg bw per day in a two-generation
    study of reproductive toxicity in rats, using a safety factor of 100.

    Toxicological evaluation

    Levels that cause no toxic effect

         Mouse:    200 ppm, equal to 35 mg/kg bw per day (13-week study of
                   toxicity)

                   50 ppm, equal to 7.8 mg/kg bw per day (haematotoxicity
                   in an 18-month study of toxicity and carcinogenicity)

         Rat:      200 ppm, equal to 13 mg/kg bw per day (13-week study of
                   toxicity)

                   100 ppm, equal to 4.8 mg/kg bw per day (haematotoxicity
                   in a two-year study of toxicity and carcinogenicity)

                   25 ppm, equal to 1.6 mg/kg bw per day (maternal
                   haematotoxicity in a two-generation study of
                   reproductive toxicity)

                   200 ppm, equal to 13 mg/kg bw per day (reproductive
                   toxicity in a two-generation study)

                   1000 mg/kg bw per day, the highest dose tested
                   (maternal, embryo-, and fetotoxicity and teratogenicity
                   in a study of developmental toxicity)

         Rabbit:   1000 mg/kg bw per day, the highest dose tested
                   (maternal, embryo-, and fetotoxicity and teratogenicity
                   in a study of developmental toxicity)

         Dog:      50 ppm, equal to 1.8 mg/kg bw per day (haemotoxicity in
                   a one-year study of toxicity)

    Estimate of acceptable daily intake for humans

         0-0.02 mg/kg bw

    Studies that would provide information useful for continued evaluation
    of the compound

         1.   Observations in humans

         2.   Studies on the mechanism of haematotoxicity

        Toxicological criteria for estimating guidance values for dietary and non-dietary exposure to tebufenozide

                                                                                                                                      

           Exposure                  Relevant route, study type, species                          Results, remarks
                                                                                                                                      

    Short-term (1-7 days)         Oral, toxicity, rat                               LD50 > 5000 mg/kg bw
                                  Dermal, toxicity, rat                             LD50 > 5000 mg/kg bw
                                  Inhalation, 4 h, toxicity, rat                    LC50 > 4.3 mg/litre
                                  Dermal, irritation, rabbit                        Not irritating
                                  Ocular, irritation, rabbit                        Minimally irritating
                                  Dermal, sensitization, guinea-pig                 Not sensitizing

    Medium-term (1-26 weeks)      Repeated dietary, 90 days, toxicity, dog          NOAEL = 2 mg/kg bw per day, primarily
                                                                                    haematotoxicity
                                  Repeated dermal, 28 days, toxicity, rat           NOAEL = 1000 mg/kg bw per day, highest dose
                                                                                    tested
                                  Repeated dietary, reproductive toxicity, rat      NOAEL = 13 mg/kg bw per day, minor reproductive
                                                                                    effects
                                  Repeated gavage, developmental toxicity,          NOAEL = 1000 mg/kg bw per day, highest dose
                                  rat and rabbit                                    tested; maternal, embryo-, and fetal toxicity
                                                                                    and teratogenicity

    Long-term (> 1 year)          Repeated dietary, 1 year, toxicity, dog           NOAEL = 1.8 mg/kg bw per day, primarily
                                                                                    haematotoxicity
                                                                                                                                      
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    Osheroff, M.R. (1991a) RH-5992: 13-Week dietary toxicity study in
    mice. Unpublished report No. 89RC-102 from Hazleton Laboratories
    America, Inc., VA, USA. Submitted to WHO by Rohm & Haas Co.,
    Philadelphia, PA, USA.

    Osheroff, M.R. (1991b) RH-5992: Four-week range-finding dietary
    toxicity study in rats. Unpublished report No. 89RC-101A from Hazleton
    Laboratories America, Inc., MD, USA. Submitted to WHO by Rohm & Haas
    Co., PA, USA.

    Osheroff, M.R. (1991c) RH-5992: 13-week dietary toxicity study in
    rats. Unpublished report No. 89RC-101 from Hazleton Laboratories
    America, Inc., VA, USA. Submitted to WHO by Rohm & Haas Co.,
    Philadelphia, PA, USA.

    Richards, J.F. (1992) RH-5992: 52-week oral (dietary administration)
    chronic toxicity study in the beagle. Unpublished report No. 90RC-206
    from Hazleton UK, North Yorkshire, United Kingdom. Submitted to WHO by
    Rohm & Haas Co., Philadelphia, PA, USA.

    Sames, J.L. & Elia, M.C. (1993) RH-75,992 technical:  Salmonella
     typhimurium gene mutation assay (Ames test). Unpublished report No.
    93R-094 from Rohm & Haas Co., Toxicology Department, Philadelphia, PA,
    USA. Submitted to WHO by Rohm & Haas Co., Philadelphia, PA, USA.

    Sames, J.L. & Elia, M.C. (1994) RH-75,992 technical:  Salmonella
     typhimurium gene mutation assay (Ames test). Unpublished report No.
    93R-236 from Rohm & Haas Co., Toxicology Department, Philadelphia, PA,
    USA. Submitted to WHO by Rohm & Haas Co., Philadelphia, PA, USA.

    Sames, J.L. & Streelman, D.R. (1991) RH-75,992 technical:  Salmonella
     typhimurium gene mutation assay (Ames test). Unpublished report No.
    9IR-167 from Rohm & Haas Co., Toxicology Department, Philadelphia, PA,
    USA. Submitted to WHO by Rohm & Haas Co., Philadelphia, PA, USA.

    Solomon, H.M. & Romanello, A.S. (1992) RH-5992: Range-finding (gavage)
    developmental toxicology study in rats. Unpublished report No.
    87R-105A from Rohm & Haas Co., Toxicology Department, Philadelphia,
    PA, USA. Submitted to WHO by Rohm & Haas Co., Philadelphia, PA, USA.

    Struble, C.B. & Hazelton, G.A. (1992a) 14C-RH-5992: Biliary excretion
    study in rats. Unpublished report No. 90RC-058 from Hazleton
    Wisconsin, Inc., WI, USA. Submitted to WHO by Rohm & Haas Co.,
    Philadelphia, PA, USA.

    Struble, C.B. & Hazelton, G.A. (1992b) 14C-RH-5992: Pharmacokinetic
    study in rats. Unpublished report No. 91RC-004 from Hazleton
    Wisconsin, Inc., WI, USA. Submitted to WHO by Rohm & Haas Co.,
    Philadelphia, PA, USA.

    Swenson, R.E. & Solomon, H.M. (1992) RH-5992: Oral (gavage)
    developmental toxicity study in rabbits. Unpublished report No.
    90R-201 from Rohm & Haas Co., Toxicology Department, Philadelphia, PA,
    USA. Submitted to WHO by Rohm & Haas Co., Philadelphia, PA, USA.

    Swenson, R.E., Gillette, D.M. & Parno, J.R. (1994) RH-75,992: Acute
    oral (gavage) neurotoxicity study in rats. Unpublished report No.
    93R-093 from Rohm & Haas Co., Toxicology Department, Philadelphia, PA,
    USA. Submitted to WHO by Rohm & Haas Co., Philadelphia, PA, USA.

    Thilagar, A. (1987) RH-75,992: Test for chemical induction of
    chromosome aberration using monolayer cultures of Chinese hamster
    ovary (CHO) cells with and without metabolic activation. Unpublished
    report No. 88RC-011 from Sitek Research Laboratories, MD, USA.
    Submitted to WHO by Rohm & Haas Co., Philadelphia, PA, USA.

    Thilagar, A. (1990a) RH-5992: Test for chemical induction of gene
    mutation at the HGPRT locus in cultured Chinese hamster ovary (CHO)
    cells with and without metabolic activation. Unpublished report No.
    89RC-097 from Sitek Research Laboratories, MD, USA. Submitted to WHO
    by Rohm & Haas Co., Philadelphia, PA, USA.

    Thilagar, A. (1990b) RH-5992: Test for chemical induction of
    unscheduled DNA synthesis in rat primary hepatocyte cultures by
    autoradiography. Unpublished report No. 89RC-098 from Sitek Research
    Laboratories, MD, USA. Submitted to WHO by Rohm & Haas Co.,
    Philadelphia, PA, USA.

    Trutter, J.A. (1992a) RH-5992: 18-Month dietary oncogenicity study in
    mice. Unpublished report No. 90RC-061 and 90RC-061A from Hazleton
    Washington, Inc., VA, USA. Submitted to WHO by Rohm & Haas Co.,
    Philadelphia, PA, USA.

    Trutter, J.A. (1992b) RH-5992: 24-Month combined dietary chronic
    toxicity and oncogenicity study in rats. Unpublished report No.
    90RC-060 and 90RC-060A from Hazleton Washington, Inc., VA, USA.
    Submitted to WHO by Rohm & Haas Co., Philadelphia, PA, USA.

    Ulrich, C.E. (1992) RH-5992 (technical): Acute inhalation toxicity
    evaluation in rats. Unpublished report No. 90RC-057 from International
    Research and Development Corporation, MI, USA. Submitted to WHO by
    Rohm & Haas Co., Philadelphia, PA, USA.

    Watanabe, K. (1992) RH-5992: Reverse mutation assay with  E. coli
    (WP2 uvr strain). Unpublished report No. 92RN-1010 from The Institute
    of Environmental Toxicology, Tokyo, Japan. Submitted to WHO by Rohm &
    Haas Co., Philadelphia, PA, USA.

    Yoshida, A. (1992) RH-5992: Blood recovery study in dogs. Unpublished
    report No. 92RC-1040 from The Institute of Environmental Toxicology,
    Tokyo, Japan. Submitted to WHO by Rohm & Haas Co., Philadelphia, PA,
    USA.
    


    See Also:
       Toxicological Abbreviations
       Tebufenozide (JMPR Evaluations 2003 Part II Toxicological)