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    CYCLOXYDIM

    First draft prepared by M. Watson
    Ministry of Agriculture, Fisheries and Food
    Harpenden, Hertfordshire, United Kingdom

    EXPLANATION

         Cycloxydim is a systemic cyclohexanedione herbicide used for
    the control of grass weeds in many agricultural and horticultural
    broad-leaved crops. Cycloxydim was reviewed for the first time by
    the present Meeting.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, and excretion

    Rats

         Radiolabelled (4,6-14C) cycloxydim was administered as both
    acid and sodium salt in toxicokinetic studies. Five Sprague-Dawley
    rats per sex were given single oral doses via stomach tube of 10 or
    300 mg/kg bw in PEG 400 for the acid and similar groups were given
    10 mg/kg bw of the sodium salt as an aqueous solution. In order to
    investigate enterohepatic circulation these experiments were
    repeated using groups of 3 males and 3 females in bile duct
    cannulated rats. The effects of repeated dosing were investigated in
    groups of 5 rats/sex given single radiolabelled doses of 10 mg/kg
    bw/days acid after 14 previous daily doses of unlabelled material at
    10 mg/kg bw/day and in groups of 3 rats of each sex given 7 daily
    doses of 10 or 300 mg/kg bw/day radiolabelled acid. Furthermore, 5
    rats per sex were given a single intravenous dose of 10 mg/kg bw
    radiolabelled sodium salt (Hawkins  et al., 1986).

         Both the acid and sodium salt were well absorbed and almost
    completely excreted within 5 days after dosing. Elimination
    proceeded predominantly via the urine with 74 to 86% of the applied
    radioactivity being excreted within 5 days. Faeces contained
    approximately 12 to 25% of the applied radiolabel. No volatile
    radiolabel was detected in expired air and less than 1% of the
    administered dose was retained in the body. In rats with cannulated
    bile ducts, 55 to 66% of the dose was excreted into the bile within
    48 h regardless of the dose level or type of formulation. In the
    same time period, renal excretion amounted to 23 to 37%, and faecal
    excretion to < 3%. Therefore, enterohepatic recirculation occurred
    in rats and almost all radioactivity excreted in faeces of intact
    rats would have been excreted via the bile. It may also be concluded
    that both excretion and bioavailability of the two types of
    formulation are comparable. The sodium salt seemed to be more
    rapidly absorbed after oral administration, but an influence of the
    different type of carrier cannot be excluded.

         After oral administration of 300 mg/kg bw to rats, normalised
    areas under plasma radiolabel concentration against time curves
    (AUCs) were approximately twice as high as after administration of
    10 mg/kg bw. This indicates a non-linear relationship between dose
    level and AUC. Following multiple oral dosing for 7 days, at
    10 mg/kg bw/day, normalized AUC figures were double compared to
    those figures obtained after single oral administration of 10 mg/kg
    bw. Following both single and multiple oral administration of

    radiolabelled cycloxydim the highest residue concentrations were
    detected in liver and kidneys. The level of residues in the various
    tissues was not influenced by single oral administration of either
    acid or sodium salt. Compared to the plasma levels, multiple dosing
    did not result in essential accumulation of radiolabel.

         Radiolabelled cycloxydim was applied to shaved skin areas of
    Sprague-Dawley rats in nominal doses of 0.014, 0.14 or 1.4 mg/cm2
    (corresponding nominally to 0.9, 9 or 90 mg/kg bw) at a constant
    dose volume of approximately 1.3 ml/kg to an area of approximately
    12 cm2 on the back. The duration of treatment at the various dose
    levels was 0.5, 1, 2, 4 and 10 h with additional groups of animals
    treated for 10 h and sacrificed at 72 h (collection of excreta for
    62 hours after removal of dermal dose). The results indicated that
    within 10 h up to 36%, 36% and 24% of radiolabel is absorbed through
    the skin at dose levels of 0.014, 0.14 and 1.4 mg/cm2
    respectively. After oral doses of 10 mg/kg bw a mean of 89.5% was
    found to be absorbed within the 10 h after treatment. With the
    exception of untreated skin, mean quantities of radiolabel in
    tissues and plasma of all dermal dose groups were at all sacrifice
    times at or below 1% of the applied dose. Unexpected high mean
    quantities of radiolabel were found consistently in untreated skin.
    The design of experiments and additional tests provided no evidence
    that cross-contamination from treated skin to untreated skin
    occurred. From data presented in this study it was concluded that
    dermal doses of 0.9, 9.0 and 90 mg/kg bw (0.014, 0.14, 1.4 mg/cm2)
    could be considered equivalent to oral doses of approximately 0.3,
    3.0 and 30 mg/kg bw, respectively, for the purpose of toxicological
    evaluation assuming that the distribution and metabolism of a dermal
    dose was the same as an oral dose (Hoffmann  et al., 1989).

    Biotransformation

    Rats

         Metabolism of cycloxydim in rats was largely unaffected by dose
    levels or dosage form (free acid or sodium salt). In all cases the
    major metabolite in urine was the sulfoxide (TSO). The next most
    important metabolite was T1SO resulting from N-de-ethoxylation of
    TSO. Other less important metabolites in urine were the sulfones of
    T1SO and T2SO (Beckmann rearranged product of T1SO). The identities
    of these major metabolites were confirmed by mass spectrometry.
    Minor components in some urine samples corresponded
    chromatographically to the sulfone of TSO and unchanged cycloxydim.
    The presence of minor metabolites hydroxylated at the 5-position of
    the cyclohexone ring of cycloxydim was indicated after oxidation and
    methylation of a urine sample. The patterns of radioactive
    components in bile and tissue residues were generally similar to the
    pattern in urine. A postulated biotransformation pathway for
    cycloxydim in the rat is shown in Figure 1.

    Toxicological studies

    Acute toxicity studies

         The results of acute toxicity studies on cycloxydim are
    summarised in Table 1. Deaths generally occurred 1-2 days after
    dosing and the non-specific signs of toxicity were characterized by
    reversibility within the observation period. The gross-pathological
    examination of the animals did not show any consistent
    substance-induced changes.

        Table 1: Acute toxicity of cycloxydim (acid)

                                                                              
    Species   Sex   Route    LD50           LD50    Reference
                             mg/kg bw       mg/l
                                                                              

    Rat       M+F   Oral     approx. 5000           Hildebrand & Kirsch (1987)
    Rat       M     Oral     4420                   Kirsch & Kieczka (1984a)
              F              3830
    Mouse     M+F   Oral     >5000                  Kirsch & Kieczka (1985a)
    Rat       M+F   Dermal   >2000                  Kirsch & Kieczka (1984b)
    Rat       M+F   Inh                     >5.28   Klimisch, et al. (1985)
    Rat       M     ip       2370                   Kirsch & Kieczka (1985b)
              F              1943
                                                                              
        Short-term toxicity studies

         Subacute toxicity studies with rats were carried out for 4
    weeks and 3 months. Mice were used as a second rodent species for 4
    weeks. Cycloxydim (as the acid or sodium salt) could not be
    administered to rodents via the feed because of insufficient
    stability nor was it possible to administer cycloxydim as the acid
    in the drinking water on account of its low solubility. After only
    one day the active ingredient concentration in the mixture of feed
    and test substance was only about 78% of the initial value, and
    after 8 days only about 50% was detected. Therefore, following
    demonstration of adequate stability by chemical analysis, the test
    substance was administered as the sodium salt via the drinking water
    in all short- and long-term investigations in rodents. In dogs the
    test substance could be administered as sodium salt in the feed
    since the mixture was prepared freshly each day shortly before
    feeding, and sufficient stability could be verified analytically for
    the short period until feed was consumed completely (food was
    generally consumed within one hour, at which time the analyzed
    concentration was 91% of intended). Altogether, 3 feeding studies
    were carried out with beagle dogs for 4 weeks, 3 months and 1 year.
    In all studies, the data in ppm or mg/kg bw refer to cycloxydim as
    acid rather than sodium salt.

    Mice

         In a 4-week range-finding study, groups of 10 B6C3F1 mice
    per sex were administered doses of 0, 300, 1000, 3000 or 9000 ppm
    cycloxydim as the sodium salt (purity 94.8%) via the drinking water.
    Drinking water consumption was reduced, in a dose dependent fashion,
    up to a maximum of 50%, whereas feed consumption and body-weight
    gain were decreased only at 9000 ppm (approximately 14%). The
    clinical chemistry examinations revealed reduced cholesterol values,
    compared to controls, at a dose of 3000 ppm and above and increased
    urea values in both sexes of the highest dose group. At the end of
    the study, an increase in the relative liver weight was observed in
    the males of all dose groups. The histopathological examination
    showed hydropic vacuolar degeneration of hepatocytes only at the
    highest dose level (Kuhborth  et al., 1986a).

         Since a NOAEL could not be determined in the previous study, a
    further range-finding study was carried out in mice of the same
    strain using a similar experimental design and doses of 0, 30, 100,
    300 or 900 ppm. The absolute and relative liver weights of the males
    were increased at doses of 100 ppm and above. Reduced drinking water
    consumption (4-9%) was observed in the females at doses of 300 ppm
    and above, but feed consumption or body-weight gain were not
    affected even at 900 ppm. Clinical chemistry values and other organ
    weights were not changed by the test substance at any dose level. No
    histopathological examinations were carried out in this study since
    no histopathological findings were detected in the first range-
    finding study in the mouse within a similar dose range. The NOAEL
    was difficult to establish since the liver weight increase occurred
    without any other indications of toxicity, such as changes in
    clinical chemistry parameters or gross-pathological or
    histopathological findings. Assuming that the organ weight change
    was indicative of toxicity the NOAEL was 30 ppm in males and 100 ppm
    in females, equal to 7 mg/kg bw/day in males and 28 mg/kg bw/day in
    females, respectively (Kuhborth  et al., 1986b).

    Rats

         In a dose range-finding study, groups of 5 Wistar rats per sex
    were administered cycloxydim as the sodium salt (purity 92.8%) for
    28 days via the drinking water at levels of 0, 300, 1000, 3000 or
    9000 ppm. At the lowest two dose levels the only difference from
    controls was a reduction in drinking water intake. On account of the
    presence of test substance in the drinking water, the isolated
    finding of reduced drinking water consumption is regarded as a
    problem of palatability rather than as a sign of toxicity of the
    test substance. Reduced feed consumption mainly in the females
    (approximately 15%), reduced drinking water consumption in general
    (approximately 20-28%) and a slight reduction in body-weight gain
    (5-12%) in the females were observed at 3000 ppm. Slightly increased
    urea levels in the blood were detected in the clinical chemistry
    examinations at 3000 ppm, along with increased relative liver

    weights in the females and increased relative kidney weights in the
    males, but there was no correlation with the histopathological
    evaluation. The highest dose of 9000 ppm showed pronounced toxicity,
    which was evident in the form of poor general state, reduced feed
    consumption (20-50%), reduced drinking water consumption (42-69%)
    and reduced body-weight gain of more than 20% compared to the
    control. The clinical chemistry examination revealed slightly
    increased urea and sodium values in both sexes, increased
    cholesterol and chloride values in the serum of the males and
    lowering of the triglyceride levels and alkaline phosphatase
    activity in both sexes compared to controls. Investigative,
    analytical studies confirmed that an apparent bilirubinaemia was due
    to test material or metabolite in serum interfering with the routine
    analytical methodology. Among the relative organ weights, the
    increased liver and kidney weights were particularly noticeable. No
    histopathological correlation was found at this dose level either.
    The changes in the clinical chemistry parameters described were
    probably due to the reduced feed and drinking water consumption and
    the resulting depression of body-weight gain. One female rat
    receiving 9000 ppm died after 11 days of treatment. Pathological
    investigations revealed heart and lung lesions which were not
    considered to be treatment-related. The NOAEL was 1000 ppm, equal to
    100 mg/kg bw/day, with the liver and kidneys being regarded as
    possible target organs (Kuhborth  et al., 1986c).

         Groups of 10 Wistar rats/sex were administered 0, 30, 100, 300,
    900 or 2700 ppm of cycloxydim as the sodium salt (purity 94.8%) in
    the drinking water for 13 weeks. A further 10 animals per sex were
    added to the control group and the groups receiving 900 or 2700 ppm
    and were maintained for a 6-week withdrawal period after completion
    of treatment. The animals tolerated 30, 100 and 300 ppm without any
    substance-induced effect. Signs of slight toxicity were observed at
    900 ppm. In the clinical chemistry examinations, the creatinine
    values were increased in the females and plasma ALAT activities were
    increased in both sexes. Plasma ALP activity was reduced in the
    males. Body-weight and feed consumption were unaffected, while the
    drinking water consumption of the females was reduced by a maximum
    of 17%. At the highest dose level of 2700 ppm a reduction in feed
    consumption (11%) and drinking water consumption (a maximum of 35%)
    were recorded. The body-weight of the males was reduced by 8%
    compared with the control group. The creatinine, urea and
    cholesterol values of the females and the plasma ALAT activity of
    both sexes were increased, while the activity of alkaline
    phosphatase in the plasma was reduced. There were no
    treatment-related changes in organ weight, gross-pathology or
    histopathological findings at any dose level. All changes described
    showed a tendency to reversibility during the 6-week withdrawal
    period. The NOAEL was 300 ppm, equal to 25 mg/kg bw/day (Kuhborth
     et al., 1986d).

    FIGURE 1

    Dogs

         In a range-finding study, 2 beagle dogs per sex and dose were
    given 0, 300, 1200, 3600 or 10 800 ppm as the sodium salt of
    cycloxydim (purity 94.8%) in their feed for 4 weeks (equal to doses
    of 0, 10, 40, 120 or 360 mg/kg bw/day). At the highest dose level,
    the feed consumption of the females was occasionally reduced, while
    body-weight remained unaffected. The plasma ALP activity and the
    plasma cholinesterase activity were increased in the males. On
    several occasions of the red blood count were marginally reduced.
    The relative liver weight was increased compared with the untreated
    control and histopathological examination showed enlargement of
    hepatocytes. The findings were less pronounced at a dose level of
    120 mg/kg bw/day. The only treatment-related findings at this dose
    were increased plasma ALP in the males and a tendency to an
    increased relative liver weight. The NOAEL in this study was 40
    mg/kg bw/day (Hellwig  et al., 1985).

         Groups of 4 beagle dogs/sex/dose were used for a subchronic
    feeding study in dogs over 13 weeks using doses of 0, 60, 300, 1500
    or 7500 ppm as the sodium salt (purity 94.8%). No findings related
    to the test substance administered were obtained at the 3 lowest
    dose levels but toxicity was pronounced at 7500 ppm. However, there
    were no clinical changes and body-weight gain remained unaffected by
    treatment. The clinical chemistry examination revealed increased
    serum activities of ALP and a reduced albumin concentration. The
    females had increased globulin values in the serum, while the sodium
    level in the blood was reduced in the males. Among the haemato-
    logical changes, the reduced erythrocyte counts and presence of
    Heinz bodies were of note. However, the number of reticulocytes and
    platelets was increased suggesting a compensatory reaction in the
    bone marrow. In the males, the MCH and MCV were also increased. Of
    the organ weights, the absolute and relative liver weights were
    above those of the untreated control in both sexes. The bile was
    reddish and histopathological examination revealed an enlargement of
    hepatocytes. The NOAEL was 1500 ppm, equal to 50 mg/kg bw/day
    (Hellwig  et al., 1986).

         In a 12-month feeding study, groups of 6 beagle dogs/sex were
    given doses of 0, 400, 1600 or 6400 ppm cycloxydim (acid) as sodium
    salt (purity 93.9%). The lowest dose of 400 ppm did not lead to any
    substance-induced changes. At 1600 ppm, the number of Heinz bodies
    was increased in both sexes, indicating a disturbance in the
    haemoglobin metabolism. Male animals showed an increased activity of
    ALP in plasma and a lowering of the albumin level. The absolute and
    relative liver weights of these animals were significantly
    increased, but no corresponding histopathological changes were
    observed. This finding was also detected in both sexes of the
    highest dose group and some further clinical chemistry parameters
    were also changed. There was an increase in plasma ALP and a
    lowering of the albumin and protein concentrations (in the males
    only). The haematological examinations showed signs of slight

    anaemia with a compensatory bone marrow reaction. These findings
    were manifest in the females in the form of haemosiderosis of
    Kupffer's cells in the liver as a histopathological correlation. The
    NOAEL was 400 ppm in the diet, equal to 20 mg/kg bw/day (Hellwig  et
     al., 1988a).

    Long-term toxicity/carcinogenicity studies

    Mice

         In a 24-month study in B6C3F1 mice, cycloxydim was
    administered as the sodium salt (purity 93.9%) in the drinking water
    at doses of 0, 10, 20, 60 or 240 ppm to groups of 50 mice/sex
    (controls 100 mice/sex). There were no clinical findings which were
    induced by the test substance. Body-weight gain, food and water
    intake and the incidence of mortality remained unaffected by
    treatment. The histopathological examination at the end of the study
    did not reveal any changes related to the test substance. The
    tumours that occurred corresponded to those of the spontaneous range
    of the animal strain used so that no carcinogenic potential of the
    test substance was apparent, up to a dose level of 240 ppm, equal to
    32 mg/kg bw/day (Kuhborth  et al., 1988c).

    Rats

         In a study to determine chronic toxicity, groups of 20 Wistar
    rats per sex/dose were administered 0, 100, 400, 1600 or 2700 ppm
    of cycloxydim as sodium salt (purity 93.9%) via the drinking water
    for 18 months. At the highest dose of 2700 ppm, reduced food and
    drinking water consumption were observed in both sexes together with
    a decrease in body-weight gain of up to 21% compared with the
    control during the major part of the study period. Doses of 400 and
    1600 ppm also led to reduced body-weight gain compared with the
    control, but drinking water consumption and feed consumption (males
    only) were reduced only at 1600 ppm. In the clinical chemistry
    examinations, a lowering of the triglyceride level was observed at
    doses of 400 ppm and above. The organ weight determinations and the
    gross pathological and histopathological examination did not reveal
    any treatment-related findings. Therefore, the NOAEL in this study
    was 100 ppm, equal to 7 mg/kg bw/day (Kuhborth  et al., 1988a).

         In a second study carried out simultaneously to clarify
    possible carcinogenicity, groups of 50 Wistar rats/sex were given
    cycloxydim as the sodium salt (purity 93.9%) in the drinking water
    for 24 months at doses of 0, 100, 400 or 1600 ppm. As in the 18-
    month study, a reduction in the drinking water consumption and body-
    weight by up to 18% was observed in both sexes at 1600 ppm, but feed
    consumption was not impaired in this study. The clinical chemistry
    examinations revealed a lowering of the triglyceride level in the
    females at 1600 ppm. The body-weight reduction (both sexes) and
    lowering of the triglyceride level (females) were also observed at a
    dose level of 400 ppm. The determination of organ weights at the end

    of the study showed a lowering of the absolute and relative liver
    weights at the high-dose, but there was no corresponding
    morphological change. No findings related to the test substance
    administered were obtained in the gross pathological or
    histopathological examinations. There was no indication of any
    disturbance of the spontaneous tumour profile of the rat strain
    used. Under the given test conditions, cycloxydim has no
    carcinogenic potential in Wistar rats. The NOAEL with regard to
    clinical or clinical chemistry parameters and organ weight changes
    was 100 ppm, the same as that of the 18-month toxicity study
    (Kuhborth  et al., 1988b).

    Reproduction study

    Rats

         Investigations of reproductive toxicity were carried out in
    Wistar rats in a multi-generation study in which 2 litters were used
    in the first generation and 1 litter in the second generation.
    Groups of 24 animals per sex were adminis-tered cycloxydim as the
    sodium salt (purity 93.9%) via the drinking water at doses of 0,
    100, 400 or 1600 ppm (expressed as acid) for a period of 70 days
    prior to mating and then throughout gestation and lactation.

         The highest dose of 1600 ppm, equal to 150 mg/kg bw/day caused
    systemic toxicity in the parental animals (reduced food and drinking
    water consumption and retarded body-weight gain). The number of all
    pups (live and stillborn) at parturition was slightly reduced and
    the development of the pups was retarded. Pup mortality was also
    increased at this dose level. At the mid-dose (400 ppm), there were
    only indications of systemic toxicity in the parental animals in the
    form of reduced food and drinking water consumption as well as
    temporary retardation of body-weight gain. There was no effect on
    the number of pups or on pup mortality at this dose. Accordingly,
    the NOAEL was 100 ppm, equal to 10 mg/kg bw/day for parental
    toxicity and 400 ppm, equal to 38 mg/kg bw/day for reproductive
    performance (Hellwig  et al., 1988b).

    Special studies on embryo/fetotoxicity

    Rats

         Cycloxydim as the sodium salt (purity 93.9%) was administered
    to 23 or 24 pregnant rats per test group by gavage from days 6 to 15
    after mating at doses of 0, 100, 200 or 400 mg/kg bw/day. On day 20
    of gestation the dams were sacrificed, and the fetuses were examined
    after caesarean section. At 100 and 200 mg/kg bw/day no signs of
    maternal toxicity were observed but body-weight gain and food
    consumption were reduced at the highest dose level at the beginning
    of test substance administration compared with the untreated
    control. The number of implant-ations and resorptions and the
    fertility rate were similar to those of the control at every dose

    level. Fetotoxic effects were observed in the range of maternal
    toxicity; they were characterized by reduced fetal body-weight and
    retardation of ossification of the skeletons of the fetuses.
    Furthermore, an increased incidence of vertebral column changes in
    the fetuses, which were classified as anomalies, was detected at the
    highest dose level. These were mainly changes in thoracic vertebrae,
    which had a dumbell-shaped or bipartite appearance. One out of 309
    fetuses at 200 mg/kg bw/day and 1/295 fetuses at 400 mg/kg bw/day
    had anal/tail defects (Hellwig & Hildebrand, 1987a).

         In a second study, maternal toxicity after administration of
    the sodium salt (purity 93.9%) was investigated in more detail.
    Groups of 25 female Wistar rats were administered cycloxydim at
    doses of 0, 200, 400, 600 or 800 mg/kg bw/day by gavage from days 6
    to 15 of gestation. The dams were sacrificed on day 20 of gestation.
    After caesarean section the fetuses were evaluated only to a limited
    extent (weight and sex determinations and gross-pathological
    examination) since the main aim of the study was to determine the
    exact maternal toxicity threshold. Pronounced maternal toxicity
    which,  inter alia, was manifest in the form of clearly retarded
    body-weight gain together with reduced food consumption was observed
    at a dose level of 800 mg/kg bw/day. The general state of health was
    poor, 5 dams showing vaginal haemorrhages. RBC parameters
    (haemoglobin content, erythrocyte count, haematocrit) were reduced,
    and the number of reticulocytes was increased compared with the
    untreated control indicating a compensatory reaction of the bone
    marrow. These findings were also obtained at 600 and 400 mg/kg
    bw/day although they were less pronounced. The NOAEL regarding
    maternal toxicity was 200 mg/kg bw/day, confirming the result of the
    first study. Fetal weight was reduced at 600 and 800 mg/kg bw/day
    and the gross-pathological examination revealed missing or
    incomplete tail in some cases together with anal atresia in 3 of 270
    fetuses (in 3 out of 22 litters) at 800 mg/kg bw/day and in 2 of 296
    fetuses (in 2 out of 24 litters) at 600 mg/kg bw/day (Hellwig  et
     al., 1987).

         A third study in Wistar rats was carried out to investigate
    whether the changes in the vertebrae which occurred in the first
    prenatal study also persisted postnatally. Two groups, each of 60
    pregnant females, were given cycloxydim (as the sodium salt, purity
    93.9%) by daily oral gavage, between days 6 and 15 of pregnancy at
    doses of 0 or 400 mg/kg bw/day. Twenty-five dams from each group
    were sacrificed on day 20 of pregnancy and their fetuses were
    examined after caesarean section. The remaining dams were allowed to
    litter and rear their pups. The litters of a further 10 dams from
    each group were sacrificed on day 7 post-partum and all other
    litters were sacrificed on day 21 after parturition and examined in
    detail. In the dams sacrificed on day 20 of gestation there were
    indications of the beginning of maternal toxicity characterised by
    retarded body-weight gain and reduced feed consumption. The weight
    of the fetuses was reduced. Four fetuses (out of 286) from 3/22
    litters had tail defects. The incidence of retarded ossification of

    the skeletons was clearly higher compared with the untreated
    control. As in the first prenatal toxicity study dumbell-shaped or
    bipartite thoracic vertebrae occurred to an increased extent
    compared with the control. The incidence of the changes in the
    thoracic vertebrae of the pups sacrificed 7 or 21 days after birth
    was clearly reduced compared with the prenatal investigations
    although these findings, which also occur spontaneously without
    relation to the test substance, were not completely reversible
    either in the untreated control or in the animals treated.
    Furthermore, perinatal mortality was slightly increased at 400 mg/kg
    bw/day compared to controls. This finding was due to an increased
    number of dead pups on the day of birth whereas the survival index
    of the pups sacrificed 7 days after birth remained unaffected
    (Hellwig & Hildebrand, 1987b).

         In addition to the  in vivo studies, an  in vitro study was
    carried out with rat embryos (whole embryo culture technique).
    Cycloxydim (acid) and the main metabolite (TSO) were investigated in
    an experiment in which embryos of Wistar rats which were 9.5 days
    old were incubated in the culture medium with the test substance or
    solvent control (DMSO) for 48 h. The concentrations were 300 g/ml
    for cycloxydim and 150 g/ml for the TSO metabolite. Concentrations
    were based on results of  in vivo teratogenicity studies in the rat
    and on investigations into the kinetics and metabolism in the same
    animal species. After incubation, the embryos were evaluated under a
    stereo-microscope and subsequently examined histopathologically for
    possible substance-induced changes. No abnormal morphological
    development was induced either by cycloxydim or by its TSO
    metabolite in the embryos under the test conditions chosen. These
    results clearly demonstrate that a direct embryotoxic effect was not
    seen  in vitro at this very sensitive development stage of the main
    organs (Neubert  et al., 1987)

    Rabbits

         Groups of 14 or 15 pregnant Himalayan rabbits were administered
    cycloxydim as the sodium salt (purity 93.9%) by daily gavage from
    days 6 to 18 after artificial insemination at doses of 0, 100, 200
    or 400 mg/kg bw/day. On day 29 of gestation, the dams were
    sacrificed and the fetuses were examined in detail after caesarean
    section. At a dose of 400 mg/kg bw/day, the dams showed a
    retardation of body-weight gain together with reduced food
    consumption primarily during the treatment period compared with the
    untreated control group. This finding was also observed after
    administration of 200 mg/kg bw/day although it was less pronounced.
    No signs of maternal toxicity were observed at 100 mg/kg bw/day.
    There were no indications of an embryotoxic effect of the test
    substance in the fetuses, except at 400 mg/kg bw/day, where there
    was a significant reduction in percentage live fetuses and an
    increase in percentage dead implants. The number of implantations
    and resorptions, the conception rate and the implantation loss were
    otherwise unaffected by treatment. Minor inter-group differences

    remained within the historical control range. The variations,
    anomalies and retardations that occurred were in the range of
    historical control data for all test groups (Merkle & Hildebrand,
    1985).

         In addition to routine X-ray examination, the skeletons of the
    control and highest dose group were additionally stained to look for
    abnormalities of the vertebrae. These investigations did not
    indicate any substance-induced changes of the vertebrae, as had
    occurred in rats at a similar dose level (Hellwig, 1986).

    Special studies on genotoxicity

         A number of genotoxicity tests have been carried out with
    cycloxydim. The results are summarised in Table 2  (in vitro) and
    Table 3  (in vivo).

    Special studies on skin and eye irritation and sensitization

         The skin irritation potential of cycloxydim (acid) was
    investigated in rabbits (White Vienna). About 0.5 ml of undiluted
    test substance was applied to the clipped, intact dorsal skin of 3
    animals per sex for 4 h under a semi-occlusive dressing. Very slight
    erythema in 4/6 animals, within 1 hour of patch removal, which was
    completely reversible within 2 days, was the only finding that was
    obtained (Kirsch & Kieczka, 1984c).

         The eye irritation potential of cycloxydim (acid) was
    investigated in rabbits (White Vienna). 0.1 Ml of the undiluted test
    substance was applied to the eyes of 3 male and 3 female animals.
    Slight conjunctival irritation (redness with lacrimation), which was
    seen in all animals one hour after treatment, and which was
    completely reversible within 8 days, was the only finding that was
    observed. Neither cornea nor iris showed any changes related to the
    test substance administered (Kirsch & Kieczka, 1984d).

         The sensitizing potential of the active ingredient was
    investigated in guinea-pigs (Pirbright White) in a maximization test
    in which 10 animals were used in each of the two control groups and
    20 animals in the test group. The two challenges carried out after
    intradermal induction with the test substance did not reveal any
    skin changes in the animals of the test group indicating that there
    was no sensitizing potential of cycloxydim under the test conditions
    chosen (Kirsch & Kieczka, 1985c).

    Observations in humans

         No information was available.

    
    Table 2: Results of in vitro genotoxicity assays on cycloxydim
                                                                                                                     
    Test system         Test object        Concentration       Purity   Results          Reference
                                                                                                                     
    Ames test           S. typhimurium     20-15000 g/plate   93.9%    Negative         Gelbke & Engelhardt (1985a)
                        TA98,TA100,        (Na salt)
                        TA1535,TA1537

    Ames test           S. typhimurium     20-5000 g/plate    NK       Negative         Gelbke & Engelhardt (1984)
                        TA98, TA100,       (acid)
                        TA1535, TA1537,
                        TA 1538

    Lymphoma forward    Mouse L5178Y       1.75-20 g/ml       93.9%    Weak, positive   den Boer & Hoorn (1985a)
    mutation assay      cells              (Na salt)                    at cytotoxic
                                                                        concentrations

    HGPRT forward       CHO cells          5-40 mg/ml          93.9%    Negative         Gelbke & Engelhardt (1986)
    mutation assay                         (Na salt)

    HGPRT forward       CHO cells          0.215-21.5 mg/ml    93.9%    Negative         den Boer & Hoorn (1985b)
    mutation assay                         (Na salt)

    Cytogenetics        CHO cells          500-5000 g/ml      NK       Weak, positive   Taalman & Hoorn (1985a)
    mutation assay                         (acid)                       in absence of
                                                                        activation

    Cytogenetics        CHO cells          2000-5000 g/ml     NK       Weak, positive   Taalman & Hoorn (1985b)
    mutation assay                         (Na salt)                    in absence of
                                                                        activation

    UDS                 Rat hepatocytes    100-2000 g/ml      NK       Negative         Cifone & Myhr (1985)
                                           (acid)

    UDS                 Rat hepatocytes    0.9-90.6 g/ml      NK       Negative         Cifone & Brusick (1985)
                                           (Na salt)
                                                                                                                     
    NK: not known

    Table 3: Results of in vivo genotoxicity assays on cycloxydim
                                                                                                                     
    Test system         Test object        Dose                Purity   Results          Reference
                                                                                                                     

    Micronucleus        NMRI mice          225, 450, 900       93.9%    Negative         Gelbke & Engelhardt (1985b)
    test                                   mg/kg bw

    Micronucleus        Chinese            500, 1700, 5000     NK       Negative         Taalman & Hoorn (1987)
    test                hamsters           mg/kg bw
                                                                                                                     

    NK: not known
    

    COMMENTS

         Cycloxydim was extensively absorbed after oral administration
    to rats and almost completely excreted within 5 days of dosing.
    Elimination proceeded predominantly via the urine (74-86% of applied
    dose), with lower levels in the faeces (12-25% of the applied dose).
    Less than 1% of an administered dose was retained in the body.
    Studies confirmed that enterohepatic circulation occurred in rats.

         The metabolism of cycloxydim has been investigated in rats and
    a biotransformation pathway has been proposed. The major metabolite
    was the sulfoxide, and the pattern of metabolites was similar in
    urine, bile and tissue residues.

         Cycloxydim has low acute oral toxicity. WHO has classified
    cycloxydim as unlikely to present acute hazard in normal use (WHO,
    1992).

         Owing to instability in dietary admixture the sodium salt of
    cycloxydim was administered in the drinking-water in repeat-dose
    rodent studies. In dogs, sufficient dietary stability was
    demonstrated, and dietary administration of cycloxydim was therefore
    used.

         In mice, two 4-week dose range-finding studies were conducted,
    followed by a 24-month long-term study. In the dose range-finding
    studies, employing concentrations between 30 and 9000 ppm, reduced
    food and water intake, and reduced body-weight gain were seen at
    higher doses, together with increased liver weight and hydropic
    vacuolar hepatocyte degeneration. The NOAEL was equal to 7 mg/kg
    bw/day in males and 28 mg/kg bw/day in females, the lower NOAEL in
    males resulting from liver weight increase in the absence of any
    histopatho-logical change. In the long-term study, no treatment-
    related effects were seen, up to the highest dose tested of 32 mg/kg
    bw/day, although liver weights were not measured.

         In rats a 4-week dose range-finding study was followed by a 13-
    week study, an 18-month toxicity study and a 24-month
    carcinogenicity study. Findings were generally similar to those
    observed in mice, the liver being identified as the only target
    organ of note, although no histopathological changes were seen at
    doses up to 900 mg/kg bw/day. The NOAELs were 100 mg/kg bw/day over
    4 weeks, 25 mg/kg bw/day over 13 weeks and 7 mg/kg bw/day over 18/24
    months, based on reduced body-weight gain at 25 mg/kg bw/day and
    above.

         Cycloxydim was not carcinogenic in rats or mice.

         In dogs, a 4-week dose range-finding study was followed by a
    13-week and a 12-month study. In the dose range-finding study (at
    doses up to 360 mg/kg bw/day) the liver and the red blood cells were

    identified as target organs and the NOAEL was 40 mg/kg bw/day. In
    the longer-term dog studies, the NOAELs were 50 mg/kg bw/day over 13
    weeks and 20 mg/kg bw/day over 52 weeks. Target organs were the
    liver and red blood cells. A marginal anaemia was seen, along with a
    compensatory bone marrow response, but no serious treatment-related
    histopathological effects were noted at 80 or 300 mg/kg bw/day.

         In a multi-generation reproduction study in rats, the NOAELs
    were about 10 mg/kg bw/day for parental toxicity and 38 mg/kg bw/day
    for reproductive performance, pup mortality being slightly increased
    at 150 mg/kg bw/day.

         Teratogenicity studies have been carried out with cycloxydim in
    rats and rabbits. In the rat teratogenicity studies the NOAEL for
    maternal toxicity was 200 mg/kg bw/day. Fetotoxicity was seen at
    maternally toxic doses, together with findings which may be
    considered indicative of a teratogenic potential (missing/incomplete
    tail and anal atresia at 600 and 800 mg/kg bw/day and vertebral
    anomalies at 400 mg/kg bw/day). Although the vertebral anomalies
    were not completely reversible post-natally (up to 21 days after
    birth),  in vitro embryo culture studies demonstrated that
    cycloxydim did not show any direct embryotoxic effects. In the
    rabbit teratogenicity study the NOAEL for maternal toxicity was 100
    mg/kg bw/day. There was no indication of fetotoxicity in rabbits,
    even in the presence of maternal toxicity and no indication of any
    treatment-related vertebral anomalies, even when a special
    examination was conducted to look specifically for such changes.

         After reviewing the available genotoxicity data, the Meeting
    concluded that cycloxydim and its sodium salt were not genotoxic.

         An ADI was allocated based upon the NOAEL from the long-term
    rat study in rats, using a safety factor of 100.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    > 240 ppm in the drinking water, equal to > 32
                        mg/kg bw/day (two-year study)

         Rat:      100 ppm in the drinking-water, equal to 7 mg/kg
                        bw/day (18- and 24-month studies)

                   100 ppm in the drinking-water, equal to 10 mg/kg
                        bw/day (multi-generation study)

                   200 mg/kg bw/day (teratogenicity study, maternal and
                        fetal toxicity)

         Dog:      400 ppm in the diet, equal to 20 mg/kg bw/day (one-
                        year study)

         Rabbit:   100 mg/kg bw/day (teratogenicity study, maternal
                        toxicity).

    Estimate of acceptable daily intake for humans:

         0-0.07 mg/kg bw

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

         Observations in humans.

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    See Also:
       Toxicological Abbreviations