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    BINAPACRYL

    EXPLANATION

         Binapacryl has been evaluated for an acceptable daily intake
    (ADI) by the Joint Meetings in 1969 and 1982 (Annex 1, FAO/WHO, 1970a
    and 1983a). A toxicology monograph was prepared by the Joint Meeting
    in 1969 (Annex 1, FAO/WHO, 1970b). In 1969 the Joint Meeting estimated
    an ADI of 0-0.0025 mg/kg b.w., based on toxicity data largely produced
    by IBT. In the absence of any validation or information concerning
    replacement studies, the 1982 Joint Meeting recommended that the
    existing ADI be withdrawn. Since then some IBT studies that were
    evaluated by the 1969 Joint Meeting have been submitted with
    accompanying validation reports. Moreover, some new studies have also
    become available. All these studies are reviewed in this monograph
    addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, excretion and metabolism

         Concentrations of radioactive compounds were measured in the
    portal blood of rats 2, 4, and 6 hours after oral administration of
    2.7 mg/kg b.w. of binapacryl-(phenyl-U-14C) or binapacryl-(acrylic
    acid-14C). The active ingredient was not detectable in the portal
    blood at any measurement time. Dinoseb (a hydrolytic product of
    binapacryl) was extracted as the only radioactive compound from the
    blood when binapacryl-(phenyl-U-l4C) was administered. On average,
    15% of the total radioactivity in the blood was extractable as free
    dinoseb with diethyl ether. After boiling for 1 hour with 1 M HC1 an
    additional 20% of the radioactivity was extracted and also identified
    as dinoseb. The remaining radioactivity could not be extracted; it
    probably consists of highly polar metabolites which are not hydrolysed
    under the conditions adopted. The dimethyl acrylic acid group was
    present in the portal blood at a lower concentration than the dinoseb
    moiety. In both tests the highest radioactivity in the portal blood
    was measured 4 hours after administration (Kunzler et al., 1980).

         Dinoseb, dinoseb acetate, binapacryl-(phenyl-U-l4C), or
    binapacryl-l4C-labelled in the dimethylacrylic acid group, were
    administered orally to rats at a dose level of 8.3 mol/kg b.w. Two,
    4 and 6 hours after administration, the portal blood was withdrawn for
    analysis and radioactivity was measured. After administration of
    dinoseb, dinoseb acetate, or binapacryl-14-C labelled in the phenyl
    ring, the total radioactivity directly extractable from the blood was

    identified as dinoseb. Additional dinoseb was extracted after
    hydrolysis of the blood samples. After administering binapacryl-14-C
    labelled in the dimethylacrylic acid group, only small quantities of
    radioactivity were absorbed by the blood; these were highly polar in
    nature. Dinoseb was most rapidly absorbed and quickly reached the
    maximum blood level. Dinoseb acetate reached a blood level similar to
    that of dinoseb but with some delay. Both moieties of the binapacryl
    molecule were transferred to the blood, but at distinctly slower rates
    and at lower levels than when dinoseb or dinoseb acetate was
    administered. As the two moieties of the binapacryl molecule (dinoseb
    and dimethylacrylic acid) were not present in the blood at equal
    levels, the authors assumed that, after slow hydrolysis of binapacryl,
    dinoseb and dimethylacrylic acid were absorbed at different rates
    (Dorn et al., 1982).

    Toxicological studies

    Special study on reproduction

         An IBT multigeneration study on binapacryl was reviewed by the
    Joint Meeting in 1969 (Annex 1, FAO/WHO, 1970b). In this study, groups
    of rats (8 males and 16 females) were fed 0, 1, or 50 ppm of
    binapacryl for three generations. The reproductive performance, as
    measured by the indices of mating, pregnancy, fertility, parturition
    and lactation, was not influenced by the feeding with binapacryl.
    Neither were the different parameters of the progeny, e.g. litter
    size, number of stillbirths, viability, survival and weight of
    weanlings. Upon weaning of the F3b litters, gross and histological
    examination of several of the animals from all groups did not reveal
    any changes attributable to binapacryl (Kennedy and Calandra,
    1965a,b,c).

         An audit validation for the three IBT reports covering this
    three-generation reproduction study in rats was submitted to the Joint
    Meeting in 1985. According to this validation, the three-generation
    reproduction study in ablino rats is a valid statement of the work
    conducted (Ellison, 1979d,e,f).

         However, in view of the many important missing data (e.g.
    pathological examinations of weanlings, individual animal and litter
    data and specifications of the test substance), the Meeting considered
    this study not to be adequate.

    Special studies on embryotoxicity and teratogenicity

         Groups of 11-12 pregnant female New Zealand rabbits received (by
    gavage) binapacryl (% a.i. not specified) at a daily-dose level of 0,
    0.2, 1.0, or 5.0 mg/kg b.w. on days 6 through 18 of pregnancy. On day
    29, dams were sacrificed and the foetuses removed for external,
    visceral and skeletal examinations.

         Mean feed and water consumption, and body weight and body-weight
    gain of dams were comparable between control and treated groups
    throughout the pregnancy period.

         There were no statistically-significant differences between
    control and treated groups with respect to mean value of corpora
    lutea, implantations, live and dead foetuses, early and late
    resorptions, or live foetal weight. Placenta weight was slightly
    decreased in the 5.0 mg/kg b.w. group, but the difference was not
    toxicologically relevant because all other findings were normal. Sex
    incidence of live foetuses was also comparable between control and
    treated groups.

         Foetuses with externally visible malformations were one in the
    control and one in the 5.0 mg/kg b.w. group. The incidence of skeletal
    variations was usual for this strain and comparable among groups. Only
    one visceral malformation was observed in the control group. Survival
    rate after 6 and 24 hours was greater in the treated groups than in
    the control. Absolute organ weight of dams was unremarkable.
    Ophtalmological examinations of eyes of the dams and histopatological
    examination of the foetal eyes gave no indication of any cataract
    development.

         The daily no-effect level for embryotoxicity/teratogenicity is
    5.0 mg/kg b.w. in this study (Korte and Osterburg, 1980).

    Special studies on mutagenicity

         Several microbiol assays carried out on binapacryl did not
    indicate any mutagenic potential (Table 1).

    Special study on cataract formation

         An IBT dog study on cataract formation (Cervenka and Kay, 1963)
    was reviewed by the 1969 Joint Meeting (FAO/WHO, 1979). This study has
    not been validated (Ellison, 1979b).

        Table 1.  Results of mutagenicity assays on binapacryl
                                                                                        

    Test organism     Test material    Range of doses    Result               Reference
                                                                                        

    S. typhimurium    Binapacryl       4-2,500           No significant       Gericke and
    TA 1535           % a.i. not       g/plate          difference of        Wasner,
    TA 1537           specified                          revertants/          1978
    TA 100                                               plate compared
    TA 98                                                to negative
                                                         control*

    S. typhimurium    Binapacryl       10-10,000         No significant       Shirasu
    TA 1535           100% a.i.        g/plate          difference of        et al.,
    TA 1537                                              revertants/          1980
    TA 1538                            TA 100 also       plate compared
    TA 100                             20,000            to control*.
    TA 98                              g/plate          A slight effect
                                                         was observed for
                                                         TA 100 at 20,000
                                                         g/plate, only
                                                         without S-9 mix.

    E. coli WP2 hcr   Binapacryl       10-10,000         No significant       Shirasu
                      100% a.i.        g/disc           difference of        et al.,
                                                         revertants/plate     1980
                                                         compared to
                                                         negative control*.

    B. subtilis       Binapacryl       20-2,000          No induction of      Shirasu
    H17 Rec+/M45      100% a.i.        g/disk           any inhibitory       et al.,
    rec-                                                 zone in either       1980
                                                         strain.

                                                                                        

    *    Both with and without S-9 mix.
    
    Acute toxicity

         Oral acute toxicity of technical binapacryl has been studied in
    several species, whereas dermal acute toxicity has only been assayed
    in rats (Table 2). Clinical signs of acute oral intoxication in mice
    include decreased spontaneous activity, lying prone, increased
    respiratory rate, discharge of yellow urine and diarrhoea. In fatal
    cases, death occurrred within 6 hours after dosing, following
    additional symptoms of sudden excitation, a rise of body temperature,

        Table 2. Acute toxicity assays on binapacryl
                                                                                                     

                                                                          LD50
    Species        Sex       Route     Test material       Vehicle        mg/kg b.w.     Reference
                                                                                                     

    Mouse          M         oral      Binapacryl techn.   gum arabic     1280           Morioka
                                                                                         et al.,1978a

    Mouse          F         oral      Binapacryl techn.   gum arabic     1650           Morioka
                                                                                         et al.,1978b

    Rat Wister     F         oral      Binapacryl techn.   starch sol.    325-350        Scholz, 1964

    Rat albino     F         oral      Binapacryl techn.   starch sol.    220-270        Scholz, 1964
    mixed breed

    Rat albino     F         oral      Binapacryl techn.   starch sol.    220            Weigand,
    mixed breed                                                                          1964

    Rat            M         oral      Binapacryl techn.   peanut oil     63             Gaines, 1969
                   F         oral      Binapacryl techn.   peanut oil     58

    Rat            F         oral      Binapacryl          starch sol.    421            Scholz and
                                                                                         Kramer, 1972

    Rat            M         dermal    Binapacryl techn.   xylene         810            Gaines, 1969
                   F         dermal    Binapacryl techn.   xylene         720

    Rat            F         dermal    Binapacryl techn.   gum arabic     >2000          Morioka,
                                                                                         1978c

    Rabbit         M+F       oral      Binapacryl techn.   starch sol.    640            Scholz, 1964

    Dog            M+F       oral      Binapacryl techn.   starch sol.    450-640        Scholz, 1964
                                                                                                     
    
    salivation, and finally extension of the hind limbs and stiffness of
    the body. All the survivors recovered to normal on the next day of
    dosing. Weight loss lasted from 1-4 days of the post-dosing period
    (Morioka et al., 1978b).

    Short-term studies

    Rat

         An IBT study in which groups of Sprague-Dawley albino rats
    (10 males and 10 females/group) were fed diets containing binapacryl
    at levels of 2, 10, 50, 250, or 500 ppm for 90 days, was submitted to
    the Joint Meeting in 1969 (Kay and Calandra, 1962). However, this
    study has not been validated by Ellison (1979c).

    Cat

         A non-validated cat dietary study is available where groups of 1
    male and 1 female domestic cats were administered binapacryl (% a.i.
    not specified) in the diet at daily-dose levels of 0, 0.25 and
    25 mg/kg b.w. for 2 years (IBT study without number, dated 24 January
    1966).

    Dog

         Groups of mongrel dogs (1 male and 1 female per group) were fed
    diets containing binapacryl (purity not specified), at concentrations
    of 25 or 50 ppm for 2 years (6 times per week). No control group was
    used. Three dogs, fed at 150 ppm, on day 3 of the experiment already
    showed paralytic symptoms in the hind legs and reduced feed
    consumption; therefore, the feeding at 150 ppm was discontinued. The
    25-ppm and 50-ppm levels produced no toxic symptoms. Behaviour, feed
    consumption and weight gains of all animals were normal. The
    haematological examinations and urinalyses (appearance, colour,
    protein and sediment) did not reveal pathological changes. No clinical
    chemistry data were available.

         Autopsy and histological examination of heart, lungs, liver,
    kidneys, stomach, intestine, spleen, adrenals, testicles or ovaries,
    and thyroid gland revealed no lesions attributable to the treatment
    (Scholz, 1962).

         An IBT dog study, where groups of 3 male and 3 female Beagle dogs
    were administered orally (gelatin capsules) binapacryl at dose levels
    of 0, 0.25, 1.25, 2.50, 5.0, or 25.0 mg/kg b.w/day for 2 years, was
    reviewed by the 1969 Joint Meeting (FAO/WHO, 1970). This study was
    validated by Ellison (1979a) and reconsidered by this Joint Meeting.
    The NOEL in this study was 0.25 mg/kg b.w., but presentation of the

    data is unsatisfactory (e.g. no individual animal data are available
    as well as no individual gross and histopathological findings).
    Therefore, the Meeting did not consider this study to be adequate
    (Baran et al., 1966b).

         Groups of 4 male and 4 female Beagle dogs were fed diets
    containing binapacryl (98.1% a.i.) at levels of 0, 0.5, 3.3, or 20 ppm
    for 2 years.

         Animals were observed daily for behaviour, general condition,
    feed and water consumption and mortality. Body weights were checked
    weekly. Reflex tests, ophtalmoscopic examination, noise test, teeth
    inspection and visible mucous membranes inspection were conducted at
    0, 3, 6, 9, 12, 18, and 24 months. Haematology, clinical chemistry,
    urinalysis, bromosulfophthalein (BSP) test and phenolsulfonphthalein
    (PSP) test were carried out at 0, 6, 12, 18, and 24 months. At the end
    of treatment all animals were sacrificed for gross and histopatho-
    logical examinations.

         All dogs survived the scheduled end of the study. There was no
    treatment-related impairment of general condition, or of feed and
    water intake. Mean body weight gain in males and females of the 20-ppm
    dietary level was lower than control. Examinations of behaviour,
    neurological condition, eyes, hearing ability, teeth and visible
    mucous membranes showed no remarkable findings or differences from the
    initial status. Relative organ weights, gross or histopathological
    findings did not suggest treatment-related effects.

         Haematology, clinical chemistry and urinalysis parameters, and
    BSP and PSP tests did not show any dose-related differences between
    control and treated groups.

         The no-effect level in this study was 3.3 ppm in the diet, equal
    to 0.22 and 0.20 mg/kg b.w. for males and females, respectively (Brunk
    et al., 1981).

    Long-term studies

    Rat

         An IBT study where groups of Charles-River COB rats (30 males and
    30 females per group) were fed diets containing binapacryl at levels
    of 0, 25, 100 or 500 pppm for 2 years (Wolf et al., 1966) was
    reviewed by the Joint Meeting in 1969. This study has not been
    validated (Ellison, 1979g).

         In another old study, which completes the 2-year rat study
    included in the 1969 evaluation, groups of cross-bred albino rats
    (20 males and 20 females/treated group; 5 males and 5 females/control
    group) were fed diets containing binapacryl (purity not specified) at
    concentrations of 0 and 500 ppm for 2 years.

         In the treated group, 15 males and 13 females died during the
    experiment (3 males and 4 females during the first six months); marked
    body weight losses and laboured breathing were observed prior to
    death; most of the animals died of putrid bronchitis or pneumonia. No
    mortality occurred in the control group. Behaviour and physical
    appearance of surviving rats were comparable between groups.

         The weight gains of the treated animals were distinctly lower as
    compared to those of the control. No effect was observed on
    haematology and urinalysis (appearance, colour, protein and sediment)
    carried out on 5 males and 5 females every six months and on all
    surviving rats at the end of study.

         The macroscopic post-mortem examination performed after
    termination of the experiment revealed pneumonia and fatty
    infiltration of the liver more frequently among treated animals.
    Histopathological examinations (heart, lungs, liver, kidneys and
    spleen) revealed purulent broncho-pneumonia in treated animals, but
    not in the untreated ones, and purulent bronchiectases, haemosiderosis
    in the spleen, brownish pigment in the epithelium of renal tubules,
    and fatty infiltration in the liver more frequently in the treated
    than untreated animals. No tumours were observed (Scholz, 1962).

         This study, however, was considered by the Joint Meeting to be
    inadequate for several reasons, including the small number of animals
    used, the small number of survivors at the end of the study, and the
    fact that only five organs were examined histopathologically.

    COMMENTS

         Additional pharmacokinetic and metabolism studies in rats
    indicate that binapacryl is rapidly absorbed following oral
    administration and showed that only dinoseb, dimethyl acrylate and
    water-soluble metabolites could be measured in the portal blood.
    Absorption occurred more slowly with binapacryl than with dinoseb.
    This suggests that decomposition of binapacryl to dinoseb occurs in
    the gastrointestinal tract.

         However, in dogs (study evaluated in 1969), appreciable amounts
    of binapacryl were measured in the kidney, liver and brain, which may
    be indicative of species differences in metabolism.

         Acute toxicity studies did not show any species, strain, or sex
    specificity.

         A no-effect level was established for embryotoxic/teratogenic
    effects in rabbits.

         The three-generation reproduction study in rats was not
    considered to be valid.

         Binapacryl did not show any mutagenic potential in several
    bacterial tests.

         Paralysis of hind-quarters was observed in dogs fed high
    (150 ppm) dietary levels of binapacryl in capsules (1969 evaluations),
    but not in a new 2-year dietary dog study at levels comparable with
    the capsule study. Paralysis of hind-quarters was not observed in rat
    studies at any dose levels.

         Apart from the new dog study, the short and long-term studies
    submitted do not conform to present-day testing standards. Some of the
    studies were considered invalid. None of the long-term studies contain
    clinical chemistry examinations.

         The Meeting concluded that the total data base is inadequate for
    establishing an ADI.

    TOXICOLOGICAL EVALUATION

         At least the following data will be required before the
    assessment of an ADI can be reconsidered:

    1.   Teratology study in rats.

    2.   Chronic toxicity/carcinogenicity studies in rats.

    3.   Carcinogenicity study in a second species.

    4.   Multi-generation reproduction study.

    5.   Pharmacokinetic studies.

    6.   Justification for the small doses administered in the rabbit
         teratology study.

    7.   In studies that were found to be invalid, possible
         neurological effects were noted. If these effects are observed in
         any of the above studies, they should be investigated further.

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    See Also:
       Toxicological Abbreviations
       Binapacryl (ICSC)
       Binapacryl (FAO/PL:1969/M/17/1)
       Binapacryl (WHO Pesticide Residues Series 4)
       Binapacryl (Pesticide residues in food: 1984 evaluations)