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    TERBUFOS

    EXPLANATION

    First draft prepared by Dr A. Moretto,
    University of Padua, Padua, Italy

         Terbufos was evaluated at the 1989 Joint Meeting.  The
    toxicological monograph was inadvertently omitted from the 1989
    Evaluations.  Therefore, the monograph is included in the 1990
    Toxicology Evaluations.

         Terbufos has insecticidal properties against a range of soil-
    dwelling and above-ground insects.  It is formulated as granules which
    are incorporated in the soil at planting, or as a subsequent side
    dressing.  It is registered in many countries for use on a range of
    crops including fruits, vegetables, cereals, oilseeds, coffee and
    sugar cane.  Use rates are usually 0.2-2 kg a.i./ha.

         Terbufos was considered for the first time by the 1989 Meeting.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

         Terbufos, 14C-labelled at the thiomethyl group, was given (200
    g) by gavage to 16 Royal Hart Wistar male rats weighing 250-280
    grams. Three animals were sacrificed 6, 12, 24 or 48 hours after
    dosing; four animals were sacrificed 168 hours after dosing.  Urine
    was collected 6, 12, 24, 48, 72, 96, 120 and 168 hours after dosing
    and faeces 12, 48, 72, 96, 120 and 168 hours after dosing.  Urinary
    excretion of metabolites peaked at 24 hours and then declined with a
    t1/2 of 15 hours.  Urine and faeces accounted for 83% and 3.5% of
    total radioactivity, respectively. Less than 0.5% of total
    radioactivity was found in organs at any of the time-points. Parent
    compound was less than 1% of total radioactivity (North, 1973).

    Toxicological studies

    Acute toxicity

         Table 1 reports the LD50  values for terbufos as determined in
    different studies and animal species. 

         In addition, experiments to assess the therapeutic effect of
    atropine and 2-PAM administration during acute intoxication with
    terbufos were performed. Terbufos (89.2% purity) was given to CFY rats
    at 2 or 5 times the subcutaneous LD50 (i.e. 9.8 or 24.5 mg/kg bw).
    Atropine alone (17.4 mg/kg bw) or in combination with 2-PAM (50 mg/kg
    bw) was injected intramuscularly after terbufos administration; the
    first injection was given within 1 hour after intoxication. Treatment
    with atropine or atropine plus 2-PAM (high-dose group only) was then
    repeated according to clinical signs during the following 22 hours.
    All rats died within 27 hours except 1 rat treated with 9.8 mg/kg bw
    terbufos and 1 rat treated with 9.8 mg/kg bw terbufos plus atropine.
    It appears that under these conditions, atropine and atropine plus 2-
    PAM give no protection against terbufos (Davies and Collins, 1974b).

         In another experiment, terbufos was given to 15 RH Wistar rats at
    1.75, 3.5, 7 or 14 mg/kg bw p.o.  Five animals were then treated with
    atropine (20 mg/kg bw) and 5 with atropine plus 2-PAM (50 mg/kg bw)
    p.o. or i.p. 0 to 6 and 24 hours after terbufos administration.
    Results show that atropine alone did not increase the LD50 of
    terbufos. The combination of atropine plus 2-PAM increased the LD50
    from 3.1-4.2 to 6.5-9.5 mg/kg bw (Fischer, 1975).  

        Table 1: Acute toxicity of terbufos technical

                                                                                       

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

                                                                                       
    Mouse        F         oral           5.0           --        American Cyanamid
                                                                  Company, 1972f;
                                                                  Morici, 1972

    Mouse        F,M       oral           3.5, 9.2      --        American Cyanamid
                                                                  Company, 1972f;
                                                                  Morici, 1972

    Rat          M         oral           1.6           --        American Cyanamid
                                                                  Company, 1972f

    Rat, Newton  M         inhalation     --            0.0061    Hoffman La Roche,
                                                                  1987

    Rat          F,M       (4 hr exp.)    --, 2.67      0.0012    Wheldon, et al., 1974
                            i.p.          1.24

    Rat          F,M       dermal         7.4, 0.97     --        Wheldon and BenDyke,
                                                                  1974a

    Rat          F,M       dermal         9.8           --        American Cyanamid
                                                                  Company, 1975

    Rat          F,M       subcutaneous   4.9           --        Davies and Collins,
                           injection                              1974a

    Rabbit       F,M       oral           1.6           --        Wheldon and BenDyke,
                                                                  1974b

    Rabbit       F,M       dermal         0.81, 0.93    --        Fischer, 1985

    Rabbit       M         dermal         1.0           --        American Cyanamid
                                                                  Company, 1972f
                                                                                       
    
    Short term studies

    Mice

         CF1 mice (10 animals/group/sex) were given 0, 1, 4 or 16 ppm of
    terbufos (96.7% purity) in the diet for 31 days. At the end of the
    treatment 5 animals per group were sacrificed for autopsy. One and six
    females from the 1 ppm and 16 ppm groups, respectively, died during
    the study.  The cause of death was unknown. The appearance and
    behaviour of all treated animals were comparable to those of controls.
    In the high-dose group there was a markedly reduced body weight gain
    (<60% of controls) and a slightly reduced food intake. Mean kidney
    weight was reduced (-12%) in females only.  ChE activities were not
    determined. The mean daily intake of terbufos was (female data in
    parenthesis): 0.218 (0.286), 0.911 (0.988), 3.30 (3.70) mg/kg b.w. in
    the 1, 4, and 16 ppm groups, respectively. The NOAEL was 4 ppm  (equal
    to 0.91-0.99 mg/kg b.w.) for 31 days (Morici, 1972).

    Rats

         RH Wistar rats (10 animals/group/sex) were given 0, 0.125, 0.5,
    or 2.0 ppm of terbufos (96.7% purity) in the diet for 31 days. At the
    end of the treatment period,  5 animals per group were sacrificed for
    autopsy, determination of ChE activity in plasma, RBC and brain, and
    haematological tests. The remaining animals were bled the following
    day for haematological studies. Ten animals (including 1 female
    control) died during the study (5 died of respiratory infection, 5
    died for unknown reasons). The appearance, behaviour, body weight
    gain, food intake, gross appearance of internal organs and
    haematological parameters were not affected by any of the treatments.
    In the high-dose group  ChE activity in plasma, RBC and brain was
    markedly reduced (to 32-72% of control activity) both in males and
    females. The mean daily intake of terbufos was (female data in
    parenthesis): 0.012 (0.012), 0.069 (0.053), 0.299 (0.212) mg/kg bw in
    the 0.125, 0.5, 2.0 ppm groups, respectively. The NOAEL was 0.5 ppm
    (equal to 0.05-0.07 mg/kg bw) (Morici, 1972).

         In another study, Sprague-Dawley rats (5 animals/group/sex) were
    given 0, 0.125, 0.250, 0.5, 1.0, 3.0 or 6.0 ppm of terbufos (90.1%
    purity) in the diet for 14 days.  Animals were observed twice daily
    and weighed weekly. At the end of the treatment period animals were
    sacrificed for autopsy.  One female of the 6 ppm group died on day 11
    and a second one was sacrificed moribund on day 13. Signs of toxicity
    were observed in both males and females at the 6 ppm dose level from
    day 2 onward and at the 3 ppm dose level from day 4 onward. No toxic
    signs were observed in the animals of the remaining groups. Body
    weight gain, food intake, and liver and kidney weights were reduced in
    the 6 ppm group. In the 3 ppm group only body weight was reduced. In
    the 1 ppm group ChE activity in plasma was reduced from day 1 (males)
    or 4 (females); it was also reduced on day 4 (males and females) and

    7 (females) in the 0.5 ppm group. RBC ChE activity was reduced from
    day 4 in the 1 ppm groups and in males of the 0.5 ppm group; females
    of the latter dose level had reduced RBC ChE activity on day 4 only.
    The mean daily intake of terbufos was equal to: 0.02, 0.04, 0.08,
    0.16, 0.49, 0.77 mg/kg bw in the 0.125, 0.250, 0.5, 1.0, 3.0, 6.0 ppm
    groups, respectively.  The NOAEL for inhibition of RBC ChE activity,
    was 0.25 ppm  of terbufos in the diet (equal to 0.04 mg/kg bw) for 14
    days (Fischer, 1978).

         In another study, Sprague-Dawley rats (20 animals/group/sex) were
    given 0, 0.125, 0.250, 0.5 or 1.0 ppm of terbufos (90.1% purity) in
    the diet for 3 months.  Animals were observed twice daily and weighed
    weekly. Haematology testing, clinical chemistry analysis and
    urinalysis were performed at week 7 and at termination (10
    animals/group/sex). Plasma and RBC ChE activities were determined on
    day 1, weeks 1 and 2, months 1, 2, and 3 and at termination.  At the
    end of the treatment period animals were sacrificed for autopsy and
    brain ChE activity determination. All animals, except 2 animals in the
    mid-dose group which died accidentally, survived the treatment.  No
    toxic signs were observed in any animals. Body weight gain, food
    intake, ophthalmoscopic observations, haematology, clinical chemistry
    and urinalysis were comparable in all groups. In the 1 ppm group ChE
    activity in plasma was reduced in males from week 1 (23-42%
    inhibition) and in females from day 1 (10% inhibition) onward (36-52%
    inhibition). RBC and brain ChE activities were not reduced.
    Histological analysis did not reveal any treatment-related alteration.
    The mean daily intake of terbufos was equal to (female data in
    parenthesis): 0.011 (0.012), 0.021 (0.023), 0.041 (0.048), 0.082
    (0.095) mg/kg b.w. in the 0.125, 0.250, 0.5, 1.0 ppm groups,
    respectively.  The NOAEL for inhibition of brain ChE activity was 1.00
    ppm (equal to 0.082-0.095 mg/kg bw) (Daly, 1979).

    Rabbits

         New Zealand white rabbits (4 animals/group/sex) were given 0,
    0.004, 0.020 or 0.1 mg/kg bw of terbufos technical or 0.2, 1  or 5
    mg/kg b.w. of terbufos granular formulation (15% a.i.) by dermal
    application for 5 days/week for 3 weeks. Test compound was dissolved
    in corn oil and applied for 6 hours/day. The skin of  animals was
    observed daily for erythema, eschar formation and edema. Mild to well-
    defined erythema was observed in all groups. Six animals of the 5
    mg/kg bw group died between days 6 and 20 of treatment. Haematology
    testing, clinical chemistry analysis and urinalysis gave similar
    results in all groups.  At the end of the treatment  animals  were
    sacrificed for autopsy but no treatment-related histopathological
    alterations were observed. Body weight gain, food intake and behaviour
    were not affected by any of the treatments. The NOAEL for terbufos
    technical dermally applied was 0.1 mg/kg bw for 5 days/week for 3
    weeks and 1 (0.15 a.i.) mg/kg bw for 5 days/week for 3 weeks for the
    15% granular formulation (Kruger and Feinman, 1973).

    Dogs

         Groups of 8-12 month-old beagle dogs (2 animals/group/sex) were
    administered terbufos (96.7% purity) in the diet calculated to give a
    dose of 0, 0.01, 0.05, or 0.25 mg/kg bw/day in the diet for 30 days.
    The test compound was dissolved in corn oil and added to the diet in
    a volume of 0.25 ml/kg bw.  At the end of the treatment animals were
    sacrificed for autopsy and determination of brain ChE activity. A
    blood sample for clinical chemistry was taken 3 days prior to dosing,
    2 weeks after beginning of treatment and at termination. All dogs
    survived the treatment without alteration in appearance and behaviour.
    Haematological parameters (excluding ChE activities) were not affected
    and no gross lesions were seen at autopsy in any animal. Body weight
    gain was significantly reduced in the animals of the 0.25 mg/kg bw
    group. RBC ChE activity was significantly reduced at 2 weeks and at
    termination in the high-dose group and in the 0.05 and 0.25 mg/kg b.w.
    groups at termination. Plasma ChE activity was significantly reduced
    in the 0.05 and 0.25 mg/kg bw groups at 2 weeks and in all treated
    groups at termination. At termination, brain  ChE activity was reduced
    in the high dose-group only (34% of control).  The NOAEL for
    inhibition of brain ChE activity was 0.05 mg/kg bw/day (Morici, 1972).

         In another study, beagle dogs (4 animals/group/sex) were given 0,
    0.0025, 0.010, or 0.040 mg/kg bw/day of terbufos  (purity not
    reported) 6 days/week for 6 months.  At the end of the treatment, 
    animals were sacrificed for autopsy and determination of brain ChE
    activity.  A blood sample for clinical chemistry was taken 3 days
    prior to dosing, 2 weeks after beginning of treatment and at
    termination.  All dogs survived the treatment without alteration in
    appearance and behaviour. One control animal died of volvulus of the
    colon. Haematological parameters and urinalysis were not affected.
    Body and organ weights were not affected and no gross lesions were
    seen at autopsy in any animal. Plasma ChE activity was inhibited by
    26% and 31% in mid and high- dose groups, respectively; RBC ChE
    activity was not significant reduced in the high-dose group. No effect
    was seen on brain ChE activity.  The NOAEL was 0.040 mg/kg bw (the
    highest dose tested) (Morgareidge, 1973).

         A study was undertaken to establish whether a 6 day/week as
    compared to a 7 days/week dosing regimen could influence the outcome
    of the previous study. Purebred beagle dogs were given 0.05 mg/kg bw
    of terbufos (88% purity) by gavage for 6 or 7 days/week for 4 weeks.
    RBC ChE activity was never significantly affected while plasma ChE
    activity was reduced on days 7, 21 and 28 of treatment in the 7
    days/week group but not in the 6 days/week group: it should be noted
    that on those days animals of the latter group were not given terbufos
    (Berger, 1977).

         In a one-year study, purebred beagle dogs were orally given 0,
    0.015, 0.06, 0.24 or 0.48 mg/kg bw/day of terbufos (89.6% purity).

    Because of high toxicity, starting from week 7 the high dose was
    reduced to 0.12 mg/kg bw and from week 8 the 0.24 mg/kg bw dose was
    reduced to 0.09 mg/kg bw.  There was a dosing error during weeks 3 and
    4 when the 0.015 and 0.06 mg/kg bw dose animals received 5.2% of the
    intended dose. Animals were observed twice daily for mortality and
    clinical signs. Body weight and food consumption were determined
    weekly. Haematological, blood biochemical and urinalysis parameters
    were determined twice during pretest period, at months 3 and 6 and at
    termination. At termination, animals were sacrificed for gross
    pathology, determination of organ weights and of brain ChE activity.

         At the 0.24 and 0.48 mg/kg bw doses animals showed clinical signs
    consistent with AChE inhibition (salivation, tremor, vomiting,
    convulsions).  At week 6 one male and one female of the high dose
    group died; at week 7 one female of the 0.24 mg/kg bw dose died, and
    at week 31 one female of the high dose group was sacrificed moribund
    with a prolapsed vagina. Body weight was reduced in the high dose
    group before reduction of the dose; it was comparable to control at
    termination. Males of the 0.24 mg/kg bw also had reduced body weight
    before reduction of the dose. Food consumption was also reduced during
    the 0.24 and 0.48 mg/kg bw/day dosing regimen. Haematological, blood
    chemistry (excluding ChE activities) and urinalysis parameters and
    organ weights at termination were not significantly altered by any of
    the treatments.  No treatment-related gross pathology alterations were
    found. Plasma ChE activity was reduced in all groups in a dose-
    dependent manner: it was 55-62% and 26-38% of the control values in
    the low and high dose groups, respectively.  RBC ChE activity was not
    significantly affected in the 0.015 and 0.06 mg/kg dose groups. It was
    reduced to 81-84%  and 72-82% of control values in male and females,
    respectively, of the 0.09 mg/kg bw group. A higher inhibition was
    found in the 0.12 mg/kg dose group where activity was 81-84% and 65-
    79% of controls in males and females, respectively. The high intra-
    and inter-individual variability of brain (cerebrum and cerebellum)
    ChE activities, prevented the establishment of an NOAEL for this
    parameter. The NOAEL for inhibition of RBC ChE activity, was 0.06
    mg/kg bw/day of terbufos (Shellenberger and Billups, 1986).

         A 28-day oral toxicity study was undertaken to establish a NOEL
    for plasma ChE activity. Terbufos (89.6% purity) was given to beagle
    dogs (n = 4/group/sex, except high dose group where n = 2) at levels
    of 0, 1.25, 5.0 or 15.0 g/kg bw/day. No clinical signs were observed.
    Brain and RBC ChE activities were not affected. Plasma ChE activity
    was slightly reduced in the 5.0 g/kg dose group; it was reduced to
    60-65% of control values in the 15 g/kg dose group. It must be
    pointed out that a great discrepancy was found in brain ChE activity
    between controls of this study and that of the one-year study: in the
    latter, activities were 191-200 U/g in the cerebrum and 445-536 U/g in
    the cerebellum, while in the 28-day study the activities were 0.816-
    0.862 U/g and 2.575-3.131 U/g, respectively (Shellenberger and Smith,
    1987).  

    Sheep

         Groups of 3 sheep were given 0, 0.01, 0.10, or 1.00  ppm of
    terbufos  (89.8% purity) in the diet for 42 days.  At the end of the
    treatment  animals were sacrificed for autopsy and determination of
    brain ChE activity.  A blood sample for haematology and clinical
    chemistry was taken  prior to dosing, 3 weeks after beginning of
    treatment and at termination. All animals survived the treatment
    without alteration in appearance and behaviour. No haematological
    parameters, including  RBC ChE activity, which was measured on days 1,
    3, 7, 14, 21 and 42, nor urinalysis, were affected. The mean daily
    intake of terbufos was: 0.0003, 0.0023, 0.0245 mg/kg bw in the 0.01,
    0.1, 1.0 ppm groups, respectively.  The NOAEL for inhibition of RBC
    ChE activity was 1 ppm of terbufos in the diet, equal to 0.0245 mg/kg
    bw/day of terbufos for 42 days  (Garces, 1977).

    Calves

         Groups of 3 Holstein calves were orally given 0.05 or 0.10 mg/kg
    bw of terbufos (97.9% purity) for 7 days. RBC ChE activity, measured
    on days 1, 3, 5 and 7 of treatment, was found significantly reduced as
    compared to pretreatment on days 5 and 7 (by 25 and 31%,
    respectively). The dose of 0.05 mg/kg bw had no effect on RBC ChE
    activity (Wang, 1972).

    Long-term/carcinogenicity studies

    Rats

         Long-Evans  rats (60 animals/group/sex) were given terbufos in
    the diet at concentrations of 0, 0.25, 1, 2 ppm for 24 months. Diets
    were prepared from pre-mix containing 100 ppm of a.i. From day 35 the
    dose of 2 ppm was increased to 4 ppm and from day 77 to 8 ppm; for
    females it was decreased to 4 ppm from day 105 onward. Toxicity
    following chronic administration and carcinogenic potential of
    terbufos were evaluated. At 3 months, 10 animals/sex/group and 10
    controls/sex were sacrificed, necropsies and histological examinations
    were performed.

         The animals in the high dose group had a lower food consumption
    and a reduced (about 20-28%) body weight. Clinical signs of
    cholinesterase inhibition  were observed in females of the high-dose
    group; the signs decreased in severity from month 4 and disappeared
    from month 18. Few females in the mid-dose group had clinical signs
    during months 5 and 6.  Only 8 males of the high-dose group displayed
    clinical signs during the last 3 months of treatment.  Mortality was
    (males-females) 38-33%, 48-26%, 57-33%, 62-60% in the control, low-,
    mid-, high-dose groups, respectively. Haematological and clinical
    chemistry parameters did not show any treatment-related alteration.
    Plasma and RBC ChE activities were significantly decreased in mid- and

    high-dose groups and randomly in the low-dose groups. Brain ChE
    activity was reduced in the high dose groups (in males by 62%, in
    females by 58%) and in females of the mid-dose group (by 10%). In the
    high dose groups, liver, kidney (males), heart (males) and thyroid
    weights were reduced. A higher incidence of exophthalmos was found in
    females of the high dose group during month 4. Terminal
    ophthalmoscopic examination revealed an increased incidence of corneal
    scars in the high-dose females possibly related to the higher
    incidence of exophthalmos observed during month 4. Histological
    examination revealed an increased incidence of bronchopneumonia,
    foreign body granulomas and gastric ulcerations in the high-dose
    animals. The incidence of neoplasms was not increased. The mean daily
    intake of terbufos was (males-females): 0.010-0.013, 0.043-0.054,
    0.329-0.215 mg/kg bw in the 0.01, 0.10, 2.00-8.00 ppm groups,
    respectively.  The NOAEL for inhibition of brain ChE activity was 0.25
    ppm of terbufos in the diet (equal to 0.010-0.013 mg/kg bw) (Rapp,
    1974; McConnell, 1983).

         In a second study, Sprague-Dawley CD rats (30 animals/sex/group)
    were given terbufos (89.6% purity) in the diet at concentrations of 0,
    0.125, 0.5 or 1 ppm for one year.

         No statistically significant effect was seen on body weight, body
    weight gain and food consumption. Haematological parameters and
    urinalysis (performed in 10 animals/group/sex at 3, 6 and 12 months)
    were not altered by any treatment. A higher number of females  of the
    high dose group had chromodacryorrhoea (7/29), excess lachrymation
    (6/29) and alopecia (10/29) as compared to controls (2/29, 2/29 and
    4/29, respectively). Mortality was (males-females) 1-1, 0-0, 2-1, 0-0
    in the control, low-, mid-, high-dose groups, respectively. Plasma ChE
    activity (determined on week 6, months 3, 6 and 12) was significantly
    decreased in high-dose males from month 6 onward (-25/29%) and in
    females throughout the test period (-33/51%). RBC ChE activity was not
    affected by any treatment. Brain ChE activity was significantly
    reduced (-8/10%) in the high dose groups. In the high dose groups,
    kidney (females) and testes weights were reduced. Ophthalmoscopic
    examination did not reveal any treatment-related alteration. Increased
    incidences of non-neoplastic or neoplastic alterations were not found.
    The mean daily intake of terbufos was (males-females): 0.007-0.009,
    0.028-0.036, 0.055-0.071 mg/kg bw in the 0.125, 0.50, 1.00 ppm groups,
    respectively. The NOAEL was 0.50 ppm of terbufos in the diet (equal to
    0.028-0.036 mg/kg bw) (Daly and Knezevich, 1987). 

    Mice

         CD-1  mice (65 animals/sex/group) were given terbufos (purity
    89.6%) in the diet at concentrations of 0, 3, 6, 12 ppm (a.i.) for 18
    months. Animals were observed twice daily for toxicity signs and
    weighed weekly until week 13, every two weeks until week 26 and every
    4 weeks afterwards. Haematological parameters were determined for 10

    animals/group/sex after 12 months and at termination. Ten
    animals/group/sex were sacrificed during week 53 and the survivors
    were sacrificed at termination for gross observation and microscopic
    examination. Animals found dead or sacrificed moribund were examined
    for gross pathological and histological alterations. Mortality was
    (males-females) 10.7-23.1%, 7.6-10.7%, 4.6-18.5%, 21.5-27.7% in the
    control, low-, mid-, high-dose groups, respectively. Body weight gain
    was reduced in males (-10%)  and females (-20%) of the high dose
    group. Transient decrease in body weight was observed in mid-dose
    groups during the first 5 weeks of treatment. Food consumption was
    random and slightly depressed in high dose animals but not in the
    other treatment groups. Haematological parameters and urinalysis were
    not altered by any treatment. No treatment-related clinical signs were
    observed.  No increased incidence of non-neoplastic or neoplastic
    alterations was found.  The NOAEL was 6 ppm in the diet (equivalent to
    0.9  mg/kg bw/day) (Silverman et al., 1986). 

    Reproduction Study

         Three successive generations of Long-Evans rats were given either
    0, 0.25 or 1.00 ppm (a.i.) of terbufos technical in the diet. Diets
    were prepared from a pre-mix containing 100 ppm of a.i.. The 3
    generations of parents were mated once, twice and once, respectively.

         F0 generation parents were mated once after a 60-day growth
    period; selected offspring from this mating were chosen to became F1
    parents. F1 parents were mated twice after an 80-day growth period
    with a 10-day resting period between matings; selected offspring (10
    males and 20 females) from the first mating (F2a) were chosen to
    become F2 parents; offspring of the second mating (F2b) were
    discarded at weaning.  F2 parents were discarded after gross
    necropsy at weaning.  The F0, F1 and F2 parents were discarded
    after their offspring were weaned.  Compound was administered to
    weanling F0 generation rats and continued uninterrupted throughout
    the successive generations.

         No compound-related effect was seen on mortality, mating
    performance, pregnancy or fertility rate. Mean body weights were
    increased in both sexes of treated groups (except in the females of
    the F0 generation) as compared to control for most weeks. The mean
    food consumption of the high dose F2 males and F1 and F2 females
    were above control values for most weeks. During gestation and
    lactation increased body weight and body weight gains were observed in
    the F0 and F1 females of both treated groups. The F2 females
    showed an increase only for the gestation period in the high-dose
    group.

         F1 parents were mated twice because survival rates and weight
    gains of F2a offspring of all groups were not within normal values. 
    Mean number of pups born alive and dead was not affected by any

    treatment. Postnatal offspring survival indices showed sporadic, non
    dose-related differences from control data. An increase of the
    percentage of litters with offspring deaths was observed in the high-
    dose groups for all matings and generations (statistically significant
    in F2a generation only) when compared to the respective control
    groups.  No differences (except in the high-dose F1 generation,
    during mating period) were observed in the weight of offspring. No
    compound-related effect was observed at necropsy. The compound intake
    was found to be 0.016-0.035 and 0.067-0.142  mg/kg bw/day in the low
    and high-dose groups, respectively.  The NOAEL was 0.25 ppm in the
    diet, equal to 0.016-0.035 mg/kg bw (Smith, 1973).

    Special studies on embryo/fetotoxicity

    Rats

         Groups (n = 24-25) of mated female rats (Charles River COBS CD)
    were given daily oral doses (0, 0.05, 0.10 or 0.20 mg/kg bw) of
    terbufos (87.8% purity)  dissolved in corn oil from day 6 through 15
    of gestation (day 0 of gestation was determined by the presence of
    copulatory plug or sperm in vaginal smear). These doses were based on
    the results of a range-finding study where all dams treated with 0.40
    mg/kg bw or more died or were sacrificed moribund (Rodwell, 1984).
    Animals were observed routinely for physical appearance, behaviour and
    body weight gain. At day 20 of gestation pups were delivered by
    caesarean section. Fetuses were weighed, sexed, inspected for external
    abnormalities and examined for visceral and bone malformations.

         No alteration of physical appearance and behaviour was observed
    in any group. All animals survived until the caesarean section. Body
    weight gain between gestation days 9 and 12 was reduced in the mid-
    dose group: this is attributed to random occurrence. A slight but not
    statistically significant reduction of body weight gain was
    demonstrated in the 0.10 and 0.20 mg/kg bw dose groups (-7% and -10%
    as compared to controls, respectively) during gestation days 12-16.
    Body weight gain remained slightly (6-7%), but not significantly
    reduced after treatment (gestation days 16-20). A slight decrease, not
    significant and not dose-related, in the mean number of viable fetuses
    was observed in the 0.10 (13.7) and 0.20 (13.6) mg/kg bw dose groups
    (control=15.0) as a result of an increased post-implantation loss in
    these groups as compared to controls. Sex ratio and fetal body weights
    were similar in all groups. No treatment-related visceral or skeletal
    abnormalities were observed. It is concluded that  there was no
    evidence of embryotoxicity or teratogenicity at any of the doses used
    (Rodwell, 1985).

    Rabbits

         Groups (n = 18) of artificially inseminated female rabbits (New
    Zealand White strain) were given daily doses (0, 0.1, 0.2, 0.4 mg/kg
    bw) of terbufos (87.8% purity) by gavage  from day 7 through 19 of

    gestation. Doses were corrected for purity. These doses were based on
    the results of a range-finding study where all dams treated with 2.0
    or 4.0 mg/kg b.w.  and 80% of dams treated with 0.7 mg/kg b.w. died
    (MacKenzie, 1984). Animals were observed routinely for physical
    appearance, behaviour and body weight gain. At day 29 of gestation
    pups were delivered by caesarean section. Fetuses were weighed, sexed,
    inspected for external abnormalities and examined for visceral and
    bone malformations.

         No alteration of physical appearance and behaviour was observed
    in any group except single episodes of lachrymation, diarrhoea,
    anorexia or lethargy. Mortality was 0, 11, 0, 33% in control, low-,
    mid- and high-dose groups respectively. In the high-dose group,
    however, 2 of the 6 deaths were due to gavage error and 2 females
    showing signs of aborting were sacrificed. No difference in body
    weight gain was observed. No dead fetuses were observed. Number of
    corpora lutea, implants and resorbed fetuses, implantation efficiency,
    sex ratio and fetal body weights were similar in all groups. No
    treatment-related visceral or skeletal abnormalities were observed.
    Delayed skeletal development (full unilateral rib, chain fusion of
    sternebrae) was seen in the high-dose group. However, only 10 of the
    18 females of the mid-dose group were pregnant and 3 of them had
    resorptions only; therefore, only 7 litters were observed. In the
    high-dose group only 10 litters were observed (6 deaths and 2 non-
    pregnant animals).  It is concluded that  there was no evidence of
    teratogenicity at any of the doses used. The dose of 0.40 mg/kg bw had
    toxic effect to dams and fetuses, the latter possibly related to
    maternal toxicity (MacKenzie, 1985).

         Because of the mortality in the high-dose group and the low
    pregnancy rate in the mid-dose group, the study was repeated.

         Groups (n = 17) of artificially inseminated female rabbits (New
    Zealand White strain) were given daily doses (0, 0.05, 0.10, 0.25,
    0.50 mg/kg bw) of terbufos (89.6% purity) by gavage  from day 7
    through 19 of gestation. Doses were corrected for purity. Animals were
    observed routinely for physical appearance, behaviour and body weight
    gain. At day 29 of gestation pups were delivered by caesarean section.
    Fetuses were weighed, sexed, inspected for external abnormalities and
    examined for visceral and bone malformations.

         An increased incidence of soft-liquid faeces was observed in the
    high dose group. All animals survived until termination. One dam in
    the 0.1 mg/kg bw and one in the 0.5 mg/kg dose groups aborted. There
    was a reduced but not statistically significant body weight gain in
    the 0.25 and 0.5 mg/kg bw groups; between gestation days 16 and 20
    there was a slight body weight loss (-0.01 kg) in the high dose group.
    No effect on food consumption was observed. Pregnancy rates were 94,
    71, 82, 77 and 88% in the 0, 0.05, 0.10, 0.25 and 0.50 mg/kg bw
    groups, respectively. At necropsy, reddened areas in the fundic region

    of the stomach were observed in two high-dose dams. Numbers of corpora
    lutea, implants and live and resorbed fetuses, implantation efficiency
    and sex ratio were similar in all groups. Fetal body weight was
    slightly but not significantly reduced (- 5%) in the high dose group.
    No treatment-related visceral or skeletal abnormalities were observed.
    It is concluded that  there was no evidence of teratogenicity at any
    of the doses used. The dose of 0.50 mg/kg bw had toxic effect to dams
    and possibly to fetuses. The NOAEL was 0.2 mg/kg bw/day (Hoberman,
    1988).

    Special studies on genotoxicity

         Terbufos was variably active in a range of in vitro assays. 
    In vivo, however, terbufos was inactive. Results are summarized in
    table 2.

    Special studies on metabolites

    Mice

         Acute oral toxicity of some metabolites of terbufos was studied
    in female mice. Data are reported in table 3.

    Dogs

         Groups of male beagle dogs (n = 4 for treated groups, n = 6 for
    controls) were given daily oral doses of terbufos or its metabolites
    for 14 days as follows: terbufos (89.6% purity) 2.5 or 250 g
    (a.i.)/kg bw, terbufos sulfoxide (metabolite no. 16) (92% purity) 5.0,
    15.0, 62.5 or 250 g (a.i.)/kg bw or terbufos sulfone (metabolite no.
    22) (90% purity) 15.0, 62.5, 250 or 1000 g (a.i.)/kg bw. Animals were
    observed for body weight, food intake, mortality, clinical signs,
    plasma and RBC ChE activities. At termination ChE activity was
    determined in brain (cerebrum and cerebellum) and gross necropsy was
    performed.  Two dogs receiving terbufos sulfone (1000 g/kg bw) died
    during the study and one was sacrificed moribund. Two of these dogs
    had intussusception of the small intestine. Animals of all high dose
    groups had reduced body weight at termination and reduced food intake
    as compared to controls, with no body weight gain during the treatment
    period. At gross necropsy, alteration of gastro-intestinal tract
    (dark, red areas, intussuseptions, prolapsed anus) were seen only in
    the high dose of terbufos sulfone and terbufos sulfoxide groups.
    Plasma ChE activity was found inhibited  in all terbufos treatment
    groups: activity was 75-82% and 24-27% of pretest values in the low
    and high dose groups, respectively.  RBC ChE activity was inhibited in
    all high dose groups (7-20% of pretest values) and in the 62.5 g/kg
    terbufos sulfoxide at termination (76% of pretest value). Cerebrum ChE
    activity was inhibited in all high dose groups (38-63% of control
    values); activities of cerebellum ChE had a high variability which

        Table 2. Results of genotoxicity assays on terbufos

                                                                                                           
    Test system              Test object         Concentration       Purity   Results    Reference
                                                                                                           

    In vitro

    Ames test                S. Typhimurium      10-1000 g/plate    88.0%    negative1  Allen, 1977
                             TA-98, 100,
                             1535, 1537

    Bacterial                WP-2uvrA            10-1000 g/plate    88.0%    negative   Allen, 1977
    mutation2 (with
    and without
    activation

    Ames test1               S. Typhimurium      50-5000 g/plate    89.6%    negative   Allen, 1985
                             TA-98, 100,
                             1535, 1537,
                             1538

    Bacterial                WP-2uvrA            10 g/plate         89.6%    negative   Allen, 1985
    mutation2 (with
    and without
    activation)

    Gene mutation            Chinese Hamster     10-75 g/ml         87.8%    negative   Allen and Johnson
    and (HGPRT-test)         ovary                                                       1983
    in vitro (with and
    without activation3)

    Chromosomal              Chinese Hamster     2.5-25 nl/ml        87.8%    negative   Thilagar, 1983
    aberration in vitro      ovary
    (with and without
    activation)

    In vivo

    DNA repair5              Rat hepatocytes     0.33-33.3           87.8%    negative   Godek, 1983

    Dominant Rats            (male Crl: CD       0.1-0.4 mg/kg       89.6%    negative   MacKenzie, 1985
    lethal test              (SD) BR)            p.o. for 5 days

    Cytogenetic              Sprague-Dawley      0.2-1.8 mg/kg       89.6%    negative   Putman, 1986
    assay in vivo            Rat i.p. bone
                             marrow
                                                                                                           

    Table 2 (continued)

    1 positive controls (2-aminofluorene, N-methyl-N'-nitro-N-nitrosoguanidine, 2-aminoacridine)
      yielded expected positive results.
    2 positive controls (N-methyl-N'-nitro-N-nitrosoguanidine) yielded expected positive results.
    3 positive controls (ethyl methane sulfonate, 7,12-dimethylbenz(a)-anthracene)
      yielded expected positive results.
    4 positive controls (cyclophosphamide, triethylenemelamine) yielded expected positive results
    5 positive controls (2-acetoaminofluorene) yielded expected positive results.
    6 positive controls (triethylenemelamine) yielded expected positive results.
    7 reduced number of viable implants at high-dose at weeks 7 and 9
    
        Table 3: Acute oral toxicity of some metabolites of terbufos on female mice

                                                                                  
    Chemical name                                  LD50         Reference
                                                   (mg/kg)
                                                                                  

    Phosphorothioic acid, S-(tert.-                1.1          American Cyanamid
    butylsulfinyl)methyl O,O-diethyl ester                      Company, 1972a

    Phosphorodithioic acid, S-(Tert.-              3.4          American Cyanamid
    butylsulfinyl)methyl O,O-diethyl ester                      Company, 1972b

    Phosphorothioic acid, S-(tert.-                3.4          American Cyanamid
    butylsulfonyl)methyl O,O-diethyl ester                      Company, 1972c

    Phosphorodithioic acid, S-(Tert.-              14.0         American Cyanamid
    butylsulfonyl)methyl O,O-diethyl ester                      Company, 1972d

    Phosphorothioic acid, S-(tert.-                2.2          American Cyanamid
    butylthio)methyl O,O-diethyl ester                          Company

    Methane, Bis(tert.-butylsulfonyl)              3670         American Cyanamid
                                                                Company, 1973a

    Methane, (tert.-butylsulfinyl)                 >2500        American Cyanamid
    (methylsulfinyl)                                            1973b
                                                                                  
    
    prevented any interpretation of the data.  The NOAEL for inhibition of
    brain (cerebrum) ChE activity, was found to be 2.5, 62.5 and 250 g/kg
    bw/day for terbufos, terbufos sulfoxide and terbufos  sulfone,
    respectively (Bailey, 1988).

    Special study on delayed neurotoxicity

         Adult hens (n = 10) were given two doses of 40 mg/kg bw of
    terbufos (96.7% purity) by gavage. The second dose was given 26 days
    after the first one. This dose was chosen based on an LD50 of 43.5
    mg/kg bw.  Positive control animals (n=10) received tri-ortho-
    cresylphosphate (TOCP) 500 mg/kg bw p.o. Animals were pretreated with
    atropine 10 mg/kg b.w. i.m. 10-15 min before the second dose of
    terbufos. Animals were observed daily for clinical signs and motility.
    Hens treated with terbufos had signs of toxicity which lasted no
    longer than 72 hours. 

         Three hens died after terbufos treatment (2 within 24 hours after
    treatment, 1 on day 12). One control animal died on day 19. TOCP-
    treated hens showed locomotor impairment beginning day 19, 3 died on

    day 26, 2 on day 28 and 1 on day 29. TOCP-treated animals received a
    second dose by mistake on day 26 and were sacrificed on day 29,
    controls and terbufos-treated hens were sacrificed, asymptomatic, on
    day 47. Histological examination of TOCP-treated animals showed
    moderate axonal degeneration in lumbosacral spinal cord.  No
    histological examination was performed in terbufos treated animals.
    Terbufos did not cause signs of delayed neurotoxicity in hens at the
    LD50 level (Smith, 1972).

    COMMENTS

         Terbufos is rapidly degraded to metabolites with similar or lower
    toxicity than the parent compound.  Excretion is mainly in the urine. 
    In a one year dietary study in rats increased mortality was not
    evident at any of the doses used (up to 1 ppm).  Slight signs of
    toxicity were evident at the 1 ppm level together with a slight, but
    statistically-significant, inhibition of brain ChE activity.  No
    increased incidence of neoplastic lesions was evident.  Based on
    inhibition of brain ChE activity, the NOAEL was 0.5 ppm in the diet
    (equal to 0.028 mg/kg bw/day).

         In a one year study in dogs, signs of ChE inhibition were seen
    following treatment with doses higher than 0.12 mg/kg bw/day given
    orally.  Doses up to and including 0.06 mg/kg bw/day did not affect
    erythrocyte ChE.  The NOAEL for inhibition of erythrocyte ChE was 0.06
    mg/kg bw/day.

         In a carcinogenicity study in mice, feeding 12 ppm caused
    toxicity:  reduced body-weight gain and a slight increase in mortality
    (ChE activity was not measured) without an increased incidence of
    neoplastic lesions.  The NOAEL was 6 ppm in the diet (equivalent to
    0.9 mg/kg bw/day).

         In a two year feeding study in rats, the following were observed
    at 1 ppm:  increased mortality in males, reduced brain (females) and
    erythrocyte (both sexes) ChE activities;  at 2-8 ppm:  signs of ChE
    inhibition,  increased incidences of bronchopneumonia, gastric
    ulceration and exophthalmos,  increased mortality and reduced organ
    weights.  Terbufos was not found to be carcinogenic in this study. 
    The NOAEL was 0.25 ppm in the diet (equal to 0.01 mg/kg bw/day).

         In a 2-generation, 2 litters per generation reproduction study in
    rats, an increase in the percentage of litters with deaths of the
    offspring was observed at 1 ppm.  The NOAEL was 0.25 ppm in the diet
    (equal to 0.016 mg/kg bw/day).

         No evidence of embryo/fetotoxicity was found in rats given doses
    up to and including 0.20 mg/kg bw/day, whereas all dams treated with
    0.40 mg/kg bw/day or more died or were sacrificed moribund.  Terbufos
    was not found to be teratogenic in rabbits when given at doses up to
    and including 0.5 mg/kg bw/day, which was toxic to the dams.  
    Terbufos did not cause signs of delayed neurotoxicity in hens when
    given at a dose level about the LD50.

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

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    6 ppm in the diet, equivalent to 0.9 mg/kg bw/day (ChE
                   activity not measured)
         Rat:      0.25 ppm in the diet, equal to 0.016 mg/kg bw/day
         Dog:      0.06 mg/kg bw/day

    Estimate of acceptable daily intake for humans 

         0-0.0002 mg/kg bw

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

         Observations in humans.

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