IPCS INCHEM Home

    CLETHODIM

    First draft prepared by
    M. Caris,
    Bureau of Chemical Safety,
    Health Canada, Ottawa, Canada

         Explanation
         Evaluation for acceptable daily intake
              Biochemical aspects
                   Absorption, distribution and excretion
                   Biotransformation
              Toxicological studies
                   Acute toxicity
                   Short-term toxicity
                   Long-term toxicity and carcinogenicity
                   Reproductive toxicity
                   Embryotoxicity and teratogenicity
                   Genotoxicity
                   Special studies
                        Skin and eye irritation and skin sensitization
                        Liver cytochrome induction
              Studies on metabolites
                   Acute toxicity
                   Short-term toxicity
                   Embryotoxicity and teratogenicity
                   Genotoxicity
              Observations in humans
              Comments
              Toxicological evaluation
         References

    Explanation

         Clethodim is a new, selective cyclohexanedione herbicide which
    is effective against a wide range of annual and perennial grasses
    and has little or no activity against broadleaf weeds and sedges. It
    exerts its activity by inhibiting acetyl coenzyme A carboxylase, an
    enzyme common to the pathways of biosynthesis of fatty acids and
    flavonoids. Interference occurs at the acetyl coenzyme A-malonyl
    coenzyme A transferase site (Rendina & Felts, 1988).

         Clethodim was considered for the first time by the WHO Expert
    Group at the 1994 Joint Meeting on Pesticide Residues.

    Evaluation for acceptable daily intake

    1.  Biochemical aspects

    (a)  Absorption, distribution and excretion

         Male and female Crl:CD(SD)BR rats were given single oral doses
    of [propyl-1-14C]-clethodim at 4.4 or 468 mg/kg bw or unlabelled
    test material at 4.5 mg/kg bw per day for 14 consecutive days before
    treatment with a single radiolabelled dose of 4.8 mg/kg bw.
    Elimination was rapid: 94-98% of the administered dose was excreted
    within 48 h after treatment. The principal route of excretion was
    the urine (87-93%), and a smaller percentage (9-17%) of the
    radioactivity was eliminated in the faeces. The mean amount of
    radioactivity excreted in expired air as carbon dioxide represented
    0.5-1% of the administered dose. Although the elimination patterns
    were similar in all groups, the rate of elimination was somewhat
    faster in animals that were administered the single low dose of 4.4
    mg/kg bw (98% eliminated within 40 h) than in those given the single
    high dose of 468 mg/kg bw (98% within 50 h). No differences in
    elimination rate were seen for animals of either sex administered
    repeated low doses of clethodim. Seven days after treatment, the
    total amount of radiolabel recovered from organs and tissues was
    less than 1% of the administered dose. The highest residual tissue
    concentrations were found in the adrenals, kidney and liver. There
    were no significant dose-related or sex-specific differences in
    tissue distribution, when expressed as a proportion of the dose
    administered, and there was no evidence of bioaccumulation (Rose  et
     al., 1988a).

         Groups of 8-10 white Leghorn laying hens were given
    [cyclohexene-4,6-14C]-clethodim at 0, 2.1 or 51.3 mg/kg bw per day
    for five consecutive days and were sacrificed about 4 h after the
    final treatment. Radioanalysis showed that 78% of the low dose and
    85% of the high dose of administered radioactivity was excreted in
    the faeces; 1.9% of the low dose and 4.2% of the high dose were
    found in the tissues. The radiolabel was distributed in the tissues
    in the following order of decreasing concentration: gastrointestinal
    tract > kidney > liver. In eggs, 0.1% of the low dose and 0.3% of
    the high dose were found; the levels were highest in egg whites,
    intermediate in shells and lowest in yolks (Lee  et al., 1988).

         A single lactating goat received [propyl-1-14C]-clethodim at
    1.16 mg/kg bw per day in alfalfa diet, in three equal daily doses of
    14.2 mg for three days and then a single dose of 14.2 mg on the

    fourth day, for a total of 10 doses. One female goat served as
    control. The treated goat was sacrificed 4 h after the final dose.
    Clethodim was rapidly absorbed: the peak blood radiocarbon
    concentration (0.273 ppm) was achieved within the first hour after
    the initial dose. The mean amount of radiolabel recovered in the
    urine represented 56% of the administered dose and that in the
    faeces, 34%. The total amount of radiolabel found in the milk, blood
    and tissues represented less than 1% of the amount administered.
    Milk contained only 0.14%; the peak concentration (0.035 ppm) was
    attained after the sixth dose. The tissues contained 0.37% and the
    blood, 0.22% of the dose. The highest residual tissue concentrations
    were detected in the liver and kidney (Rose  et al., 1988b).

    (b)  Biotransformation

         The proposed metabolic pathways for clethodim in rats are
    depicted in Figure 1. It is postulated that once clethodim has been
    absorbed it can be (i) oxidized to clethodim sulfoxide (dominant
    process), (ii) converted to the  S-methyl via a sulfonium cation
    intermediate, (iii) cleaved at the oxime N-O bond to generate imine
    or (iv) hydroxylated at the 5 position.

         In the study described above in which male and female
    Crl:CD(SD)BR rats were given single oral doses of [propyl-1-
    14C]-clethodim or unlabelled material (Rose  et al., 1988a), a
    supplementary group of male rats were given a single oral dose of
    450 mg/kg bw radiolabelled compound to ensure a sufficiently large
    quantity of labelled metabolites. Urine and faeces were collected
    and analysed for the parent compound and its metabolites. The
    metabolic profiles of males and females in all dose groups were
    remarkably similar. Nine urinary metabolites were identified and
    characterized. The major metabolite was clethodim sulfoxide
    (representing 65-75% of the administered dose), and smaller amounts
    were found of the imine sulfoxide (6-13%), the sulfone (1-3%), the
    5-hydroxy sulfoxide/sulfone (0.5-1.5%) and the oxazole sulfone
    (0-5%). The primary faecal metabolites, which accounted for more
    than 1% of the radiolabel, were identified as clethodim sulfoxide
    and the imine sulfoxide. Minor (present as < 1% of the dose)
    urinary and faecal metabolites were the oxazole sulfoxide, the
    demethyl sulfoxide and the aromatic sulfone. Other minor faecal
    metabolites were clethodim sulfone, the trione sulfoxide and
    c-olefins. Parent clethodim accounted for about 1% of the
    administered dose (Rose  et al., 1988a).

    FIGURE 01

         Two groups of eight white Leghorn laying hens were given daily
    doses of [cyclohexene-4,6-14C]-clethodim at 2.1 or 51.3 mg/kg bw
    per day by capsule for five consecutive days. The hens were
    sacrificed about 4 h after the final dose, and tissues were
    collected for analysis. Two major metabolites, clethodim sulfone and
    clethodim sulfoxide, were identified in tissues and eggs. Clethodim
    sulfone accounted for up to 57% of tissue levels of radiolabel,
    whereas clethodim sulfoxide accounted for 10-31%. Clethodim
    sulfoxide was the principal metabolite in egg white (26-82%) and
    yolk (25-37%); parent clethodim was detected in significantly
    smaller amounts in both tissues and eggs. The proposed metabolic
    pathway in chickens was different from and considered to be simpler
    than that observed in rats and goats, since none of the imine,
    5-hydroxy or S-methyl analogues was detected in chickens (Lee  et
     al., 1988).

         In the study described above in which a lactating goat received
    [propyl-1-14C]-clethodim (Rose  et al., 1988b), hind- and
    forequarter muscle, peritoneal and subcutaneous fat, liver, kidneys,
    heart and blood were collected to allow characterization of
    metabolites. The major urinary metabolite was clethodim sulfoxide,
    which accounted for 67% of the urinary radiocarbon. Other urinary
    radiolabelled components were identified as clethodim (3-27%) and
    the demethyl sulfoxide (12-18%),  S-methyl (7-13%), imine sulfoxide
    (1.5-2.8%), sulfone (1.5-2.2%) and 5-hydroxy sulfoxide (0-3%). In
    the milk, about half of the radiocarbon could be extracted into
    organic solvents and occurred in clethodim, clethodim sulfoxide and
    clethodim demethyl sulfoxide; the other half of the radiocarbon was
    water soluble and was shown to be 14C-lactose. In blood and
    tissues, the maximal extractable radiocarbon residues accounted for
    77-95% of the radiolabel and were identified as clethodim and the
    sulfoxide, demethyl sulfoxide, imine sulfoxide, sulfone and
    5-hydroxy sulfone. The proposed metabolic pathway in goats was
    essentially the same as that proposed for rats (Rose  et al.,
    1988b).

    2.  Toxicological studies

    (a)  Acute toxicity

         Technical-grade clethodim has been tested for acute toxicity in
    mice, rats and rabbits. The results are summarized in Table 1.
    Clethodim was virtually non-toxic after oral or dermal
    administration to rabbits or after inhalation by rats. Slight to
    moderate toxicity was observed in mice and rats treated orally, with
    LD50 levels of 1360-2570 mg/kg bw. Clethodim administered
    intraperitoneally was moderately toxic to rats, with a combined
    LD50 for the two sexes of 1117 mg/kg bw.

    (b)  Short-term toxicity

    Mice

         Groups of 10 male and 10 female Charles River CD-1 mice were
    fed diets containing technical-grade clethodim (purity, 83.3%) for
    four weeks at 100, 250, 625, 1500 or 4000 ppm, equivalent to 0, 15,
    38, 94, 225 or 600 mg/kg bw per day. A slight anaemic process was
    manifested in male mice as a decreased erythrocyte count at >
    1500 ppm, decreased haemoglobin at > 625 ppm and lowered
    haematocrit at 4000 ppm. Increased liver weights, which were
    correlated microscopically with centrilobular hypertrophy, were
    observed in males fed 1500 ppm and in animals of each sex treated at
    the highest dose of 4000 ppm. An increased incidence of focal
    coagulative necrosis of the liver was recorded in males treated at
    > 1500 ppm. Treatment appeared to have no effect on survival,
    clinical signs, body weight or food consumption. The NOAEL was 250
    ppm, equivalent to 38 mg/kg bw per day, on the basis of the
    dose-related decrease in erythroid parameters at dietary levels >
    625 ppm (Cox & Slabik, 1986).

    Rats

         Technical-grade clethodim (purity, 83.2%) was applied in
    carboxymethylcellulose and Tween 80 to the skin of groups of six
    male and six female Crl:CD BR rats at doses corresponding to 0, 10,
    100 or 1000 mg/kg bw per day for 6 h/day, five days per week for
    four weeks, for a total of 21 exposures. A dose-related increase in
    the occurrence of skin irritation was observed at all dose levels.
    Clinical signs seen at 1000 mg/kg bw per day were described as
    anogenital discharge and staining of the fur, alopecia and red nasal
    discharge. At the highest dose, group mean body weights,
    corresponding weight gains and feed efficiency values were decreased
    in males, and increased liver weights were recorded in females. In
    males, a slight increase was observed in kidney regeneration, which
    was described as a minimal multifocal lesion. Although this finding
    was observed only in treated rats, evidence of chronic progressive
    nephropathy is not uncommon in this strain of rat and was not

    considered to represent a treatment-related effect. The NOAEL for
    systemic toxicity under the conditions of this study was thus 100
    mg/kg bw per day (Cushman  et al., 1987a).

        Table 1.  Acute toxicity of technical-grade clethodim in male and female rodents
                                                                                              
    Species,         Route and vehicle   LD50            Purity         Reference
    strain                               (mg/kg bw)      (%)
                                                                                              

    Mouse, CD-1      Oral;               M: 2570         83.3           Cox & Zoetis, 1986
                     Tween 80 + CMC      F: 2430         (technical)

    Rat, Crl:CD      Oral;               M: 1630         83.3           Cushman  et al., 1986d
     (SD)BR          Tween 80 + CMC                      (technical)

    Rat, Crl:CD      Intraperitoneal;    M: 1040         NR             Cox, 1988
     (SD)BR          Tween 80 + CMC      F: 1200

    Rat,             Inhalation          M&F:            83.3           Griffis  et al., 1986
     Sprague-Dawley                      > 3.9 mg/l      (technical)

    Rabbit, New      Oral;               M: > 2000 and   82.5           Dougherty  et al., 1989
     Zealand         Tween 80 + CMC      < 5000          (technical)
     white                               F: > 5000

    Rabbit, New      Dermal              M&F: > 5000     83.3           Cushman  et al., 1987b
     Zealand                                             (technical)
     white
                                                                                              

    NR, not reported; Tween 80, 0.5% polyoxyethylenesorbitan monooleate; CMC,
    carboxymethylcellulose
    
         In a preliminary five-week study, groups of 10 male and 10
    female Crl:CD(SD)BR rats were treated with technical-grade clethodim
    (purity, 83.4%) at dietary levels of 0, 5, 200, 1000, 4000 or 8000
    ppm, equal to 0.3, 13, 66, 261 or 515 mg/kg bw per day for males and
    0.3, 14, 71, 291 or 554 mg/kg bw per day for females.
    Treatment-related effects were decreased body-weight gain and food
    consumption (particularly during the first week of the study) in
    animals of each sex at 4000 and 8000 ppm; increased liver weights at
    > 4000 ppm; and slight to mild centrilobular hypertrophy in males
    at 1000 ppm and in animals of each sex at 4000 and 8000 ppm.
    Dose-related, statistically significant decreases in haemoglobin
    concentration were noted in males at > 1000 ppm and in
    haematocrit in males at > 4000 ppm. Raised cholesterol
    concentrations were recorded in males receiving 8000 ppm, and raised
    serum uric acid levels were seen in females given > 4000 ppm.
    Treatment had no effect on survival, clinical signs or urinary

    parameters. The NOAEL in this study was 200 ppm, equal to 13 mg/kg
    bw per day, on the basis of decreases in erythroid parameters and
    centrilobular hypertrophy of the liver at 1000 ppm and more (Cisson
    & Eisenlord, 1986).

         Technical-grade clethodim (purity, 84%) was administered to
    groups of 12 male and 12 female Crl:CD(SD)BR rats for 13 weeks at
    dietary levels of 0, 50, 500, 2500 or 5000 ppm, equal to 2, 25, 134
    or 280 mg/kg bw per day for males and 3, 30, 160 or 340 mg/kg bw per
    day for females. In order to study the reversibility of potential
    treatment-related effects, an additional 12 rats of each sex were
    assigned to the groups receiving 0, 2500 and 5000 ppm and were kept
    for a six-week recovery period after the end of treatment with
    clethodim. Significantly decreased body weights and weight gains
    were recorded in males treated with 2500 ppm and in animals of each
    sex treated with 5000 ppm. Decreased mean food consumption was noted
    in both males and females at 5000 ppm. Significantly ( p < 0.05)
    increased concentrations of cholesterol, total protein and globulin
    recorded in males fed 5000 ppm were within the normal control range
    of variability. Increased liver weights and increased incidence and
    severity of centrilobular hypertrophy of the liver were noted in
    males and females fed 2500 and 5000 ppm. A slightly increased
    incidence of renal focal regeneration was seen in males treated at
    > 2500 ppm. The pathologist did not consider this finding to be
    related to treatment; rather, these lesions were regarded as typical
    of the earliest minimal stage of spontaneous chronic progressive
    nephropathy. Treatment did not affect survival, clinical signs,
    ophthalmoscopic or haematological parameters or the results of
    urinalysis. No treatment-related effects were seen after the
    six-week recovery period. The NOAEL was 500 ppm, equal to 25 mg/kg
    bw per day, as determined by an increased incidence of hepatic
    centrilobular hypertrophy and decreased body-weight gain in animals
    of each sex treated at 2500 ppm and above (Dougherty  et al.,
    1987).

    Dogs

         Groups of four male and four female beagle dogs received
    gelatin capsules containing technical-grade clethodim (purity,
    83.3%) orally at 0, 1, 25, 75 or 125 mg/kg bw per day for 13 weeks.
    Treatment affected blood chemistry in females, which had increased
    cholesterol levels at 75 mg/kg bw per day and above and increased
    alkaline phosphatase activity at 125 mg/kg bw per day. An increased
    globulin concentration, with a concomitant decrease in the
    albumin:globulin ratio, was noted in males treated at 125 mg/kg bw
    per day. Significantly ( p < 0.05) increased total leukocyte
    counts were seen in males and decreased activated partial
    thromboplastin time was seen in females after one month at 75 and
    125 mg/kg bw per day. As no similar differences from control values
    were seen, however, after two or three months of treatment, and the
    only differences seen were in one sex, the significance of these

    findings is doubtful. Increased liver weights were recorded in males
    and females fed 75 or 125 mg/kg bw per day. Slight increases in the
    severity of cytoplasmic vesiculation and vacuolation of the
    centrilobular hepatocytes were seen in animals of each sex treated
    at 125 mg/kg bw per day. Treatment did not affect survival, clinical
    signs, ophthalmoscopic parameters, body weight or food consumption.
    The NOAEL was 25 mg/kg bw per day on the basis of elevated
    cholesterol levels and increased liver weights at 75 mg/kg bw per
    day and above (Daly & Knezevich, 1987).

         In a one-year study, groups of six male and six female beagle
    dogs were administered technical-grade clethodim (purity, 83.3%) in
    gelatin capsules at doses of 0, 1, 75 or 200-300 mg/kg bw per day.
    In the absence of any signs of overt toxicity, the high dose of 200
    mg/kg bw per day was increased after seven weeks of treatment to 300
    mg/kg bw per day. Significant effects on haematological parameters
    were seen, expressed as increased platelet and leukocyte counts in
    females at 75 mg/kg bw per day and in males and females at 300 mg/kg
    bw per day. At 300 mg/kg bw per day, erythroid parameters
    (erythrocyte, haemoglobin and haematocrit values) were decreased in
    animals of each sex, and reticulocyte and segmented neutrophil
    counts were increased in females. Treatment-related effects on blood
    chemistry were seen as increased levels of cholesterol,
    triglycerides, alkaline phosphatase and alanine aminotransferase in
    males and females at 300 mg/kg bw per day. Decreased serum glucose
    concentrations were noted in both males and females at the high dose
    and in females treated at 75 mg/kg bw per day. Increased liver
    weights were recorded in animals of each sex at 75 and 300 mg/kg bw
    per day. Significantly ( p < 0.05) increased thyroid weights seen
    in males at 300 mg/kg bw per day were not correlated with any
    microscopic changes. Histopathological alterations in animals of
    each sex treated at 300 mg/kg bw per day included hepatocellular
    enlargement, increased granular pigment (which was not associated
    with bile, iron or acid-fast lipofuscin) and slight hypercellularity
    of the bone marrow; the last finding was also observed in one male
    and one female at 75 mg/kg bw per day. The significance of a
    slightly increased incidence of pigment (not otherwise
    characterized) in the spleen of females receiving 75 or 300 mg/kg bw
    per day was uncertain. Treatment did not affect survival, clinical
    signs, ophthalmoscopic parameters, body weight, food consumption or
    the results of urinalysis. The NOAEL was 1 mg/kg bw per day on the
    basis of treatment-related effects on haematological and blood
    chemical parameters, increased liver weight and hypercellularity of
    the bone marrow at 75 mg/kg bw per day and above (Cox & Zoetis,
    1988a).

    (c)  Long-term toxicity and carcinogenicity

    Mice

         Technical-grade clethodim (purity, 83.3%) was administered in
    the diet to groups of 60 male and 60 female Crl:CD-1 (ICR)BR mice
    for 78 weeks at 0, 20, 200, 1000 or 2000-3000 ppm, equivalent to 3,
    30, 150 or 300-450 mg/kg bw per day. The high dose was increased to
    3000 ppm after 15 weeks of treatment, when haematological assessment
    did not show the significant decrease in erythrocyte parameters seen
    in the four-week preliminary study. Ten mice of each sex were
    sacrificed after 52 weeks of treatment in each group for interim
    assessment. A significant ( p < 0.05) trend to decreased survival
    was noted among males and females fed 3000 ppm, with survival at 78
    weeks of 58, 66, 60, 52 and 32% males and 67, 84, 80, 59 and 48%
    females, respectively. The predominant cause of death at this dose
    was increased incidence and severity of systemic amyloidosis.
    Decreased erythrocyte counts were recorded in animals of each sex at
    3000 ppm, with concomitant decreases in haemoglobin and haematocrit
    values in males. After 52 weeks of treatment, increased liver
    weights and centrilobular hypertrophy of the liver were observed in
    males at 1000 ppm and in males and females at 3000 ppm. Increased
    pigment, described as morphologically compatible with haemosiderin
    and bile, was noted in males at 3000 ppm. After 78 weeks of
    treatment, the hepatic changes included increased liver weights in
    females at 3000 ppm, centrilobular hypertrophy and increased pigment
    in both males and females at 1000 and 3000 ppm and bile-duct
    hyperplasia in males at > 1000 ppm. An increased incidence of
    multifocal, amphophilic alveolar lung macrophages was also observed
    in animals of each sex treated at > 1000 ppm. No significant
    effect was seen on body weight, food consumption or clinical signs.
    The NOAEL was 200 ppm, equivalent to 30 mg/kg bw per day, on the
    basis of hepatic changes, notably centrilobular hypertrophy,
    increased pigment and bile-duct hyperplasia, and an increased
    incidence of alveolar macrophages in the lungs of mice treated at
    1000 ppm and above. There was no evidence that clethodim has
    carcinogenic potential (Cox & Zoetis, 1988b).

    Rats

         Groups of 65 male and 65 female Crl:CD (SD)BR rats were
    administered technical-grade clethodim (purity, 83%) in the diet at
    levels of 0, 5, 20, 500 or 2500 ppm, equal to 0.2, 0.6, 16 or 86
    mg/kg bw per day for males and 0.2, 0.7, 21 or 110 mg/kg bw per day
    for females, for two years. Ten rats of each sex in each group were
    sacrificed after one year. After two years, 47, 49, 46, 50 and 33%
    of males and 55, 58, 51, 40 and 49% of females were still alive in
    the five dose groups, respectively. Treatment did not affect cause
    or time of death, clinical signs, ophthalmoscopic or haematological
    parameters or the results of clinical chemistry or urinalysis.
    Body-weight gain and food consumption were significantly decreased

    in animals of each sex during the first year of treatment with 2500
    ppm. Food intake, calculated relative to body weight, was slightly
    greater in males and females at 2500 ppm than in the other treated
    groups. At interim sacrifice after one year, increased liver weights
    and slight to mild centrilobular hypertrophy were noted in rats of
    each sex fed 2500 ppm. Increased liver weights seen in females at
    500 ppm were not correlated with any microscopically discernible
    change. At terminal sacrifice, liver weights of females at 2500 ppm
    were increased; males had no significant increase in liver weight,
    and no treatment-related centrilobular hypertrophy was seen in
    animals of either sex. Females treated at 2500 ppm had a slightly
    greater (12%) incidence of binucleated cells in the liver than the
    controls (2%), but the effect was of uncertain toxicological
    significance. Clethodim at dietary levels up to 3000 ppm showed no
    evidence of carcinogenic potential. The NOAEL was 500 ppm, equal to
    16 mg/kg bw per day, on the basis of decreased body-weight gain,
    decreased food intake, increased liver weight and associated
    centrilobular hypertrophy at 2500 ppm (Dougherty  et al., 1988a).

    (d)  Reproductive toxicity

    Rats

         In a preliminary study, groups of eight male and eight female
    Crl:CD(SD)BR rats were fed technical-grade clethodim (purity, 83.3%)
    at dietary levels of 0, 500, 2000 or 5000 ppm, equivalent to 25, 100
    or 250 mg/kg bw per day, for one week before and during mating.
    Males were sacrificed after mating, whereas females were treated
    throughout gestation and up to day 7 of the lactation period for a
    single litter. Parental animals of each sex that received 5000 ppm
    had decreased body-weight gain and food intake ( p < 0.05, only in
    males). Mean pup weights and corresponding weight gains were
    decreased at all dietary levels. No adverse effects on reproductive
    parameters were evident at the highest dose (McKensie, 1986).

         In a two-generation (one litter per generation) study, groups
    of 30 male and 30 female Crl:COBS CD(SD) rats were treated with
    technical-grade clethodim (purity, 83%) at dietary levels of 0, 5,
    20, 500 or 2500 ppm, equal to 0.1, 1.4, 39 or 190 mg/kg bw per day
    for males and 0.2, 1.8, 45 or 220 mg/kg bw per day for females. Mean
    body weight was decreased at 2500 ppm in both males and females of
    the F1 generation and in males of the F0 generation. Occasional
    significant ( p < 0.05) decreases in food consumption were
    recorded in F1 males and females treated with 2500 ppm. Treatment
    had no effect on parental survival, clinical signs, organ weights or
    histopathological manifestations; there were no adverse effects on
    reproductive indices (mating, fertility, pregnancy and gestation);
    and there was no effect on litter size, sex ratio, pup weight or pup
    viability. A significant ( p < 0.05) increase in the number of
    stillborn pups was observed in the litters of F1 dams treated at
    2500 ppm; however, this finding was not considered to be related to

    treatment, since the value was within the historical control range,
    and no similar increase was seen in the subsequent F2 litter. The
    NOAEL for parental systemic toxicity was 500 ppm, equal to 39 mg/kg
    bw per day, on the basis of decreased body weights and food
    consumption at 2500 ppm. The NOAEL for adverse effects on
    reproduction in the F0 and F1 generations was 2500 ppm, the
    highest dietary level tested, equal to 190 mg/kg bw per day (Tellone
     et al., 1987).

    (e)  Embryotoxicity and teratogenicity

    Rats

         In a preliminary range-finding study, groups of 10 mated female
    Crl:CD(SD) rats were given technical-grade clethodim (purity, 82.6%)
    in Tween 80 and carboxymethylcellulose by gavage at 0, 50, 150, 300
    or 500 mg/kg bw per day during days 6-15 of gestation. The day on
    which evidence of mating was observed was designated day 0 of
    gestation. Clinical signs of toxicity were an increased incidence of
    excessive salivation in females at 300 and 500 mg/kg bw per day, and
    slightly decreased body-weight gain, decreased mean number of
    uterine implantations and decreased mean fetal body weights at 500
    mg/kg bw per day. External examination of the fetuses failed to
    reveal any gross findings related to treatment (Schroeder & Daly,
    1986).

         Groups of 25 mated female Crl:CD(COBS) rats were treated with
    technical-grade clethodim (purity, 82.6%) in Tween 80 and
    carboxymethylcellulose daily by gavage at 0, 10, 100, 350 or 700
    mg/kg bw per day during days 6-15 of gestation. The day on which
    evidence of mating was observed was designated day 0 of gestation.
    Treatment with clethodim at 350 mg/kg bw per day and more decreased
    maternal body weight. Toxicity was manifested at 700 mg/kg bw per
    day as increased mortality (20%), decreased food intake and clinical
    signs of poor physical condition, including red nasal discharge,
    chromodacryorrhoea and staining of the anogenital region. Excessive
    salivation was observed in females treated at 350 and 700 mg/kg bw
    per day. Significantly decreased fetal weights and increased
    incidences of fetuses with skeletal variations or at least one
    ossification variation were recorded at 350 mg/kg bw per day and
    more. The skeletal variations were apparent as definite delays in
    ossification and were identified by incompletely or unossified
    vertebral elements (thoracic, sacral, caudal) and unossified fifth
    and/or sixth sternebrae. Treatment at the highest dose, 700 mg/kg bw
    per day, induced a significant increase in the number of fetuses
    (8/221; 3.6%) and litters (6/18; 33.2%) with external malformations,
    comprising primarily an increased incidence (seven fetuses in six
    litters) of tail defects characterized by short, filamentous or
    absent tails. An imperforated anus was recorded in two fetuses in
    two litters at this dose. Visceral malformations (exencephaly,
    defects of the lung, aortic arch and large intestine, absence of

    kidneys, bladder or ureter) were observed in four fetuses in three
    litters of dams exposed to 700 mg/kg bw per day but not in
    concurrent or historical controls (5032 fetuses in 806 litters; 38
    studies). Three of the four fetuses with visceral malformations also
    had external malformations. The NOAEL for maternal and developmental
    toxicity was 100 mg/kg bw per day. The NOAEL for teratogenicity was
    350 mg/kg bw per day on the basis of an increased incidence of
    malformations, particularly tail defects, observed at the maternally
    toxic and lethal dose of 700 mg/kg bw per day (Schroeder & Daly,
    1987).

    Rabbits

         In a range-finding study, groups of eight artificially
    inseminated female New Zealand white  Hra: specific-pathogen-free
    rabbits were treated by gavage with clethodim (purity, 83.3%) in
    Tween 80 and carboxymethylcellulose at 0, 50, 150, 300 or 500 mg/kg
    bw per day on days 7-19 of gestation. The day of insemination was
    designated day 0 of gestation. Maternal toxicity was seen at all
    doses as decreased body-weight gain and food consumption. An
    increased incidence of alopecia was recorded at 150 mg/kg bw per day
    and more. Dried faeces and gastrointestinal lesions (hairball and/or
    ulceration of the gastric mucosa) were observed at doses of 300
    mg/kg bw per day and more. In the groups given 300 and 500 mg/kg bw
    per day, two of seven pregnant rabbits died, apparently due to
    concomitant weight loss, decreased food intake, gastrointestinal
    lesions and/or abortion. In the group given 500 mg/kg bw per day,
    four of seven rabbits aborted, and one rabbit delivered prematurely.
    Data on litters of dams given 500 mg/kg bw per day could not
    effectively be evaluated, as only one female survived to term; dams
    given 300 mg/kg bw per day had an increased incidence of resorption
    and decreased litter weights when compared with the controls
    (Dearlove  et al., 1986).

         Groups of 20 artificially inseminated female New Zealand white
     Hra specific-pathogen-free rabbits were administered
    technical-grade clethodim (purity, 83.3%) in Tween 80 and sodium
    carboxymethylcellulose by gavage at doses of 0, 25, 100 or 300 mg/kg
    bw per day on days 7-19 of gestation. The day of insemination was
    designated day 0 of gestation. Mean body weights, corresponding
    weight gains and food consumption were decreased in dams given 100
    or 300 mg/kg bw per day. An increased incidence of dried faeces was
    also noted at 100 mg/kg bw per day and more; the presence of a red
    substance on the cage pans of the dams at 300 mg/kg bw per day was
    considered to be related to gastrointestinal and/or rectal
    irritation. Treatment had no adverse effect on survival, the
    abortion rate, pre- or post-implantation loss, the number of live
    fetuses, fetal weight or the fetal sex ratio. A slight increase in
    the incidence of minor skeletal alterations, comprising angulation
    of one or both hyoid alae, irregular ossification of the skull and
    nasal passages, was observed at 300 mg/kg bw per day; however, in

    the absence of a clear dose-response relationship, no direct
    correlation with treatment could be concluded. Clethodim was not
    teratogenic at doses up to 300 mg/kg bw per day. The NOAEL for
    maternal toxicity was 25 mg/kg bw per day, and that for
    developmental toxicity was 300 mg/kg bw per day (Dearlove  et al.,
    1987).

    (f)  Genotoxicity

         The results of assays for mutagenicity of technical-grade
    clethodim are presented in Table 2. The compound did not induce gene
    mutation in bacteria  in vitro. Clethodim of unknown purity
    (Putnam, 1986a) induced chromosomal aberrations in Chinese hamster
    ovary cells in the absence of exogenous metabolic activation, but a
    purified preparation did not (Putnam, 1986b). Clethodim at doses
    sufficiently high to cause acute lethality did not induce
    micronuclei in bone-marrow cells of rats treated  in vivo, and it
    did not induce unscheduled DNA synthesis in hepatocytes of mice
    treated  in vivo.

    (g)  Special studies

     (i)  Skin and eye irritation and skin sensitization

         Technical-grade clethodim (purity, 83.2%) was applied at a dose
    of 0.5 ml under occluded conditions to two intact and two abraded
    sites on the shorn backs of each of 12 female New Zealand white
    rabbits for 4 h. Slight erythema, observed immediately after dosing,
    was followed 24-72 h later by slight-to-severe erythema and
    slight-to-moderate oedema. General clearance was seen by 14 days.
    The primary irritation score was 0.7. The test material was
    considered to be slightly irritating to rabbit skin (Cushman  et
     al., 1986b).

         Undiluted technical-grade clethodim (purity, 83.3%) was
    instilled at a dose of 0.1 ml into the conjunctival sac of one eye
    of each of nine male New Zealand white rabbits, the other eye
    serving as a control. The eyes of three of the nine rabbits were
    rinsed after a 30-sec exposure. No corneal opacity or iritis was
    observed. In the six rabbits with unrinsed eyes, conjunctival
    irritation was moderate to severe 1 h after dosing and slight to
    moderate 24 h after dosing; all eyes were clear after 72 h. In the
    rinsed eyes, conjunctival irritation was moderate at 1 h and slight
    at 24 h; all eyes were clear at 48 h. The test material was
    considered to be mildly irritating to the rabbit eye (Cushman  et
     al., 1986a).


    
    Table 2.  Genotoxicity of technical-grade clethodim
                                                                                                                    
    End-point         Test system            Concentration              Purity (%)   Resultsa        Reference
                                                                                                                    

    In vitro
    Reverse mutation  S. typhimurium TA98,   0.1-10 mg/plate            83.3         Negativea       Carver  et al.,
                      100, 1535, 1537                                   (technical)                  1986b
                      E. coli WP2 uvrA

                      S. typhimurium TA98,   0.1-10 mg/plate            83.3         Negativea       Carver  et al.,
                      100, 1535, 1537                                   (technical)                  1986a

    Reverse mutation  S. typhimurium TA98,   0, 0.1, 0.33, 1.0,         91.1         Negativea       Machado  et al.,
                      100, 1535, 1537        3.33, 10 mg/plate          (technical)                  1990
                      E. coli WP2 uvrA

    Chromosomal       Chinese hamster        0.03, 0.1, 0.3, 1.0 Ál/ml  NR           Negativeb       Putnam, 1986a
    aberration        ovary CHO-K1           0.6, 0.8, 1.0, 1.2 Ál/ml                Positivec at
                      CCI 61 cells                                                   1.0, 1.2 Ál/ml

    Chromosomal       Chinese hamster        0.03, 0.1, 0.3, 1.0 Ál/ml  96.1         Negativea       Putnam, 1986b
    aberration        ovary CHO-K1           0.6, 0.8, 1.0, 1.2 Ál/ml   (purified)
                      CCI 61 cells

    In vivo
    Chromosomal       Male and female        0, 150, 500, 1500          83.3         Negative        Putnam, 1987
    aberration        Sprague-               mg/kg bw,                  (technical)
                      Dawley rats            single oral dose

    Unscheduled       Male B6C3F1            0, 100, 1000, 5000         83.3         Negative        Mirsalis &
    DNA synthesis     mice                   mg/kg bw, gavage           (technical)                  Steinmetz, 1986
                                                                                                                    
    NR, not reported
    a In the presence and absence of metabolic activation
    b In the presence of metabolic activation
    c In the absence of metabolic activation


    
         Technical-grade clethodim (purity, 83.4%) did not appear to
    sensitize the skin of male Hartley albino guinea-pigs when tested by
    the modified Buehler test (Cushman  et al., 1986c).

     (ii)  Liver cytochrome induction

         Groups of eight male Crl:CD BR rats were treated by gavage with
    technical-grade clethodim (purity, 83.8%) in carboxymethylcellulose
    and Tween 80 at 0 or 250 mg/kg bw per day for 21 consecutive days.
    Liver samples taken at sacrifice were assayed for cytochrome P450
    activity. Treatment did not affect survival, clinical signs or body
    weight. The weights of the livers of animals of each sex were
    significantly increased (20-23%), and enlarged livers were observed
    upon gross examination of two treated animals. Although the mean
    cytochrome P450 and hepatic protein contents were significantly
    greater in treated animals than controls, the mean concentrations of
    hepatic cytochrome P450 per milligram of protein or per gram of
    liver were not significantly increased. These results may reflect
    increased liver weight and do not provide evidence that clethodim
    induces liver cytochrome P450 (Beatty  et al., 1989).

    3.  Studies on metabolites

         The imine sulfone and the 5-hydroxy sulfone of clethodim
    occurred in larger amounts in plants than in rats (Rose  et al.,
    1988a). Ancillary studies on these metabolites are summarized in
    Table 3.

    (a)     Acute toxicity

         Five female Crl:CD(SD)BR rats were given a single oral dose of
    1.4 g/kg bw of the imine sulfone of clethodim. One animal had
    decreased motor activity 4 h after dosing and was dead the next day
    (Dougherty  et al., 1988b).

         Groups of five female Crl:CD (SD)BR rats received the 5-hydroxy
    sulfone of clethodim or technical-grade clethodim as a single oral
    dose of 1.4 g/kg bw. There were no clinical signs of toxicity, and
    all animals treated with the 5-hydroxy sulfone survived the 14-day
    observation period after dosing. All five rats treated with
    clethodim showed overt signs of toxicity, noted as salivation,
    decreased motor activity, collapse, hyperactivity, tremors,
    diarrhoea, dehydration and nasal, ocular, oral and anogenital
    discharge, and all died within three days of dosing (Dougherty  et
     al., 1988c).

    (b) Short-term toxicity

         The imine sulfone of clethodim was administered daily in the
    diet to groups of 10 male and 10 female Crl:CD (SD)BR rats at 0,
    100, 1000 or 8000 ppm, equal to 6.7, 71 or 600 mg/kg bw per day, for
    five weeks. Body weight and food consumption were significantly
    decreased during the first week of treatment in males given 8000
    ppm. Other effects observed only at 8000 ppm were increased serum
    cholesterol levels in animals of each sex, increased reticulocyte
    counts in males and increased liver weights in males and females in
    the absence of related histopathological alterations. Treatment did
    not affect survival, clinical signs or ophthalmoscopic parameters.
    The NOAEL was 1000 ppm, equal to 71 mg/kg bw per day (Beatty  et
     al., 1988a).

         Groups of 10 male and 10 female Crl:CD (SD)BR rats were fed the
    5-hydroxy sulfone of clethodim daily at dietary concentrations of 0,
    100, 1000 or 8000 ppm, equal to 5.9, 68 or 590 mg/kg bw per day, for
    five weeks. No signs of toxicity were seen at any dose. On the basis
    of the absence of any effects on survival, clinical signs, body
    weight, food consumption, haematological, blood chemical or
    histopathological changes, or organ weights, the NOAEL was greater
    than 8000 ppm, equal to 590 mg/kg bw per day (Beatty  et al.,
    1988b).


    
    Table 3.  Effects of clethodim and its imine sulfone and 5-hydroxy sulfone
                                                                                                                      
    Study                  Clethodim                              Imine sulfone                 5-Hydroxy sulfone
                                                                                                                      

    Acute toxicity;        3/5 deaths (Cushman et al., 1986d)     1/5 deaths                    0/5 deaths
    female rat;            5/5 deaths (Dougherty et al., 1988c)   (Dougherty et al., 1988b)     (Dougherty et al.,
    1.4 g/kg bw                                                                                 1988bc)

    Five-week dietary;     Decreased body weight and              Decreased body weight and     No treatment-related
    male & female rats     food intake, slight anaemia,           food intake, increased        effects; NOAEL,
                           increased liver weights,               liver weights, cholesterol    > 588mg/kg bw per day
                           liver hypertrophy at 4000 and          and reticulocytes at 8000     (Beatty et al., 1988b)
                           8000 ppm; anaemia, liver               ppm. NOAEL, 71 mg/kg bw per
                           hypertrophy at 1000 ppm                day (Beatty et al., 1988a)
                           NOAEL, 13 mg/kg bw per day
                           (Cisson & Eisenlord, 1986)

    Teratogenicity; rats   Maternal and fetal toxicity            Maternal toxicity at 100      Clinical signs and
                           at 350 and 700 mg/kg bw per            and 700 mg/kg bw per day;     slightly decreased
                           day; NOAEL, 100 mg/kg bw               fetal effects at 700 mg/kg    fetal body weights at
                           per day. Increased incidence           bw per day                    700 mg/kg bw per day
                           of tail malformations at               NOAEL, 10 mg/kg bw            NOAEL, 100 mg/kg
                           700 mg/kg bw per day                   per day (Hoberman &           per day (Hoberman &
                           (Schroeder & Daly, 1987)               Christian, 1988a)             Christian, 1988b)

    Microbial gene         Negative                               Negative                      Negative
    mutation               (Carver et al., 1986a,b)               (Carver et al., 1988)         (Carver eta[., 1987)

    Chromosomal            Positive in absence of                 Negative                      Negative
    aberration,            metabolic activation                   (Putnam, 1988a)               (Putnam, 1988b)
    CHO cells              (Putnam, 1986a)
                                                                                                                      


    
    (c) Embryotoxicity and teratogenicity

         Groups of 10 pregnant female Crl:CD (SD)BR rats were treated by
    gavage with the imine sulfone of clethodim in Tween 80 and
    carboxymethylcellulose at doses of 0, 10, 100 or 700 mg/kg bw per
    day during days 6-15 of gestation. Maternal toxicity was seen at the
    high dose of 700 mg/kg bw per day, manifested as excessive
    salivation and decreased body weight and food consumption.
    Significant decreases in maternal body weight were also recorded at
    100 mg/kg bw per day. At 700 mg/kg bw per day, fetal weights were
    decreased, and there were increased incidences of fetuses and
    litters with cervical ribs and delayed sternal ossification. The
    NOAEL for maternal toxicity was 10 mg/kg bw per day on the basis of
    reduced body weights at 100 mg/kg bw per day and more. An increased
    incidence of fetal variations at the maternally toxic dose of 700
    mg/kg bw per day resulted in an NOAEL of 100 mg/kg bw per day for
    developmental toxicity (Hoberman & Christian, 1988a).

         Groups of 10 pregnant female Crl:CD (SD)BR rats were
    administered the 5-hydroxy sulfone of clethodim in
    carboxymethylcellulose and Tween 80 by gavage at 0, 10, 100 or 700
    mg/kg bw per day on days 6-15 of gestation. At 700 mg/kg bw per day,
    one female showed excessive salivation and two females had rales; a
    slight decrease in fetal body weights in this group, although not
    statistically significant, was possibly related to treatment. No
    teratogenicity was seen at any dose. The NOAEL for maternal and
    fetal toxicity was 100 mg/kg bw per day (Hoberman & Christian,
    1988b).

    (d)  Genotoxicity

         Neither the imine sulfone nor the 5-hydroxy sulfone of
    clethodim induced gene mutation in  Salmonella typhimurium TA98,
    TA100, TA1535 or TA1537 or in  Escherichia coli WP2  uvrA in the
    presence or absence of metabolic activation. Neither metabolite
    induced chromosomal aberrations in Chinese hamster ovary cells.

    4.  Observations in humans

         No information was available.

    Comments

         Clethodim was readily absorbed by rats after oral
    administration. Excretion was rapid and occurred predominantly via
    the urine, with lesser amounts eliminated in the faeces and as
    carbon dioxide. There were no significant dose-related or
    sex-specific differences in elimination pattern or tissue
    distribution, and there was no evidence of bioaccumulation.

         The dominant metabolic pathway proposed for clethodim in rats
    is oxidation to clethodim sulfoxide. Other postulated pathways are
    cleavage of the N-O bond to form the imine, conversion of the
    S-ethyl group to S-methyl, formation of the oxazole, and
    hydroxylation at the 5 position. The urinary metabolites identified
    were the sulfoxides and sulfones of clethodim and 5-hydroxy
    clethodim, the sulfoxides of the imine and S-methyl clethodim and
    the sulfone of the oxazole.

         Clethodim had slight to moderate acute oral toxicity in the rat
    and mouse. WHO has not classified clethodim with regard to toxic
    hazard.

         The primary effect of treatment with clethodim after short- and
    long-term dietary exposure in the mouse, rat and dog was on the
    liver. Hepatic effects were manifest as increased liver weights and
    centrilobular hypertrophy. A study in rats administered clethodim at
    250 mg/kg bw per day did not provide evidence for liver cytochrome
    P450 induction.

         In a four-week study in mice given dietary concentrations of 0,
    100, 250, 625, 1500 or 4000 ppm, the NOAEL was 250 ppm, equivalent
    to 38 mg/kg bw per day on the basis of evidence of slight anaemia at
    625 ppm and above. In a 78-week study of toxicity and
    carcinogenicity in which mice received dietary levels of 0, 20, 200,
    1000 or 2000-3000 ppm, the NOAEL was 200 ppm, equivalent to 30 mg/kg
    bw per day, on the basis of hepatic effects and an increased
    incidence of alveolar lung macrophages at 1000 ppm and above.

         In a five-week study in which rats received dietary levels of
    0, 5, 200, 1000, 4000 or 8000 ppm, the NOAEL was 200 ppm, equal to
    13 mg/kg bw per day, on the basis of liver hypertrophy and evidence
    of slight anaemia at 1000 ppm and above. A 13-week study at dietary
    concentrations of 0, 50, 500, 2500 or 5000 ppm and a two-year
    feeding study at dietary levels of 0, 5, 20, 500 or 2500 ppm in rats
    revealed an NOAEL of 500 ppm, equal to 25 mg/kg bw per day in the
    first study and equal to 16 mg/kg bw per day in the second. The
    NOAEL was based on decreased body weights and liver hypertrophy at
    dietary levels of 2500 ppm and above.

         In dogs, 13-week oral administration of capsules of clethodim
    at doses of 0, 1, 25, 75 or 125 mg/kg bw per day resulted in an

    NOAEL of 25 mg/kg bw per day, on the basis of increased liver weight
    and cholesterol levels at 75 mg/kg bw per day and above. In a
    one-year study at doses of 0, 1, 75 or 200-300 mg/kg bw per day, the
    NOAEL was 1 mg/kg bw per day on the basis of treatment-related
    effects on the liver at 75 mg/kg bw per day and above.

         Clethodim was not carcinogenic when fed to mice or rats at
    dietary levels of up to 2500 ppm.

         A two-generation study of reproductive toxicity in rats treated
    with clethodim at dietary levels of 0, 5, 20, 500 or 2500 ppm did
    not reveal any adverse effects on reproduction. The NOAEL was 500
    ppm, equal to 39 mg/kg bw per day, on the basis of decreased
    parental body weights and food consumption at 2500 ppm.

         Studies of teratogenicity were conducted with clethodim in rats
    at doses of 0, 10, 100, 350 or 700 mg/kg bw per day and in rabbits
    at 0, 25, 100 or 300 mg/kg bw per day. In rats, the NOAEL for
    maternal toxicity was 100 mg/kg bw per day. Fetal toxicity was
    observed at the maternally toxic doses of 350 and 700 mg/kg bw per
    day. An increased incidence of malformations, specifically tail
    defects (short, filamentous or absent tails), was observed at the
    maternally toxic and lethal high dose of 700 mg/kg bw per day. In
    rabbits, maternal toxicity was observed at 100 and 300 mg/kg bw per
    day, resulting in an NOAEL of 25 mg/kg bw per day. There were no
    adverse effects on the rabbit fetus and no evidence of teratogenic
    potential at doses up to 300 mg/kg bw per day.

         Clethodim was adequately tested for genotoxicity in a series of
    assays  in vivo and  in vitro. The Meeting concluded that
    clethodim was not genotoxic.

         Although the imine sulfone and 5-hydroxy sulfone metabolites of
    clethodim have been reported to occur in higher amounts in plants
    than in animals, neither of the metabolites was more toxic than the
    parent, clethodim, in studies of acute or short-term toxicity and
    teratogenicity. There was similarly no evidence of genotoxic
    potential.

         An ADI was established on the basis of the NOAEL of 1 mg/kg bw
    per day from the one-year study in dogs and a safety factor of 100.

    Toxicological evaluation

    Levels that cause no toxic effect

         Mouse:    200 ppm, equivalent to 30 mg/kg bw per day (78-week
                   study of toxicity and carcinogenicity) 

         Rat:      500 ppm, equal to 16 mg/kg bw per day (two-year study
                   of toxicity and carcinogenicity)

         Rabbit:   25 mg/kg bw per day (study of teratogenicity)

         Dog:      1 mg/kg bw per day (one-year study of toxicity)

    Estimate of acceptable daily intake for humans

         0-0.01 mg/kg bw

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

         Observations in humans

    References

    Beatty, P.W., Bagos, A.D., Richter, W.R. & Wong, Z.A. (1988a)
    Five-week oral toxicity study in rats with RE-47719 (SX-1800).
    Project No. 2949. Unpublished report dated 15 November 1988 from
    Chevron Environmental Health Center Inc., Richmond, CA, USA.
    Submitted to WHO by Tomen Pacific Agro Co., San Francisco, CA, USA.

    Beatty, P.W., Bagos, A.C., Richter, W.R. & Wong, Z.A. (1988b)
    Five-week oral toxicity study in rats with RE-51228 (SX-1803).
    Project No. 2950. Unpublished report dated 15 November 1988 from
    Chevron Environmental Health Center Inc., Richmond, CA, USA.
    Submitted to WHO by Tomen Pacific Agro Co., San Francisco, CA, USA.

    Beatty, P.W., Brorby, G.P. & Wong, Z.A. (1989) The potential of
    RE-45601 Technical (SX-1688) to induce cytochrome P-450 following
    21-day oral administration in male rats. Project No. 2784.
    Unpublished report dated 16 November 1989 from Chevron Environmental
    Health Center Inc., Richmond, CA, USA. Submitted to WHO by Tomen
    Pacific Agro Co., San Francisco, CA, USA.

    Carver, J.H., Machado, M.L. & Richter, W.R. (1986a)
    Microbial/mammalian microsome mutagenicity plate incorporation assay
    with RE-45601 Technical (83% purity, SC-1688). Project No. SOCAL
    2505. Unpublished report dated 13 January 1986 from Chevron
    Environmental Health Center Inc., Richmond, CA, USA. Submitted to
    WHO by Tomen Pacific Agro Co., San Francisco, CA, USA.

    Carver, J.H., Machado, M.L. & Richter, W.R. (1986b)
    Microbial/mammalian microsome mutagenicity plate incorporation assay
    with RE-45601 Technical (83% purity, SC-1688). Project No. CEHC
    2555. Unpublished report dated 28 April 1986 from Chevron
    Environmental Health Center Inc., Richmond, CA, USA. Submitted to
    WHO by Tomen Pacific Agro Co., San Francisco, CA, USA.

    Carver, J.H., Machado, M.L. & Richter, W.R. (1987)
    Microbial/mammalian microsome mutagenicity plate incorporation assay
    with RE-51228. Project No. 2856. Unpublished report dated 7 December
    1987 from Chevron Environmental Health Center Inc., Richmond, CA,
    USA. Submitted to WHO by Tomen Pacific Agro Co., San Francisco, CA,
    USA.

    Carver, J.H., Machado, M.L. & Richter, W.R. (1988)
    Microbial/mammalian microsome mutagenicity plate incorporation assay
    with RE-47719. Project No. 2948. Unpublished report dated 19 October
    1988 from Chevron Environmental Health Center Inc., Richmond, CA,
    USA. Submitted to WHO by Tomen Pacific Agro Co., San Francisco, CA,
    USA.

    Cisson, C.M. & Eisenlord, G.H. (1986) Five-week pilot feeding study
    in rats with RE-45601 Technical (SX-1653). Project No. SOCAL 2457.

    Unpublished report dated 7 October 1986 from Chevron Environmental
    Health Center Inc., Richmond, CA, USA. Submitted to WHO by Tomen
    Pacific Agro Co., San Francisco, CA, USA.

    Cox, R.H. (1988) Acute intraperitoneal toxicity study in rats with
    Chevron RE-45601 Technical (SX-1688). Project No. 2107-151.
    Unpublished revised report dated 6 April 1988 from Hazelton
    Laboratories America Inc., Vienna, VA, USA. Submitted to WHO by
    Tomen Pacific Agro Co., San Francisco, CA, USA.

    Cox, R.H. & Slabik, C.M. (1986) Four-week subchronic oral toxicity
    study in mice with Chevron RE-45601 Technical. Project No. 2107-140.
    Unpublished report dated 21 July 1986 from Hazelton Laboratories
    America Inc., Vienna, VA, USA. Submitted to WHO by Tomen Pacific
    Agro Co., San Francisco, CA, USA.

    Cox, R.H. & Zoetis, T. (1986) Acute oral toxicity study in mice with
    Chevron RE-45601 Technical. Project No. 2107-143. Unpublished report
    dated 16 September 1986 from Hazelton Laboratories America Inc.,
    Vienna, VA, USA. Submitted to WHO by Tomen Pacific Agro Co., San
    Francisco, CA, USA.

    Cox, R.H. & Zoetis, T. (1988b) One-year oral toxicity study in dogs
    with Chevron RE-45601 Technical (SX-1688). Project No. 2107-153.
    Unpublished report dated 28 October 1988 from Hazelton Laboratories
    America Inc., Vienna, VA, USA. Submitted to WHO by Tomen Pacific
    Agro Co., San Francisco, CA, USA.

    Cox, R.H. & Zoetis, T. (1988b) Chronic oral oncogenicity study in
    mice with Chevron RE-45601 Technical (SX-1688). Project No.
    2107-145. Unpublished report dated 25 October 1988 from Hazelton
    Laboratories America Inc., Vienna, VA, USA. Submitted to WHO by
    Tomen Pacific Agro Co., San Francisco, CA, USA.

    Cushman, J.R., Thompson, J.D. & Wong, Z.A. (1986a) The acute eye
    irritation potential of RE-45601 Technical (SX-1688). Project No.
    CEHC 2511. Unpublished report dated 1 October 1986 from Chevron
    Environmental Health Center Inc., Richmond, CA, USA. Submitted to
    WHO by Tomen Pacific Agro Co., San Francisco, CA, USA.

    Cushman, J.R., Korenaga, G.L. & Wong, Z.A. (1986b) The four-hour
    skin irritation potential of RE-45601 Technical (SX-1688). Project
    No. CEHC 2512. Unpublished report dated 18 December 1986 from
    Chevron Environmental Health Center Inc., Richmond, CA, USA.
    Submitted to WHO by Tomen Pacific Agro Co., San Francisco, CA, USA.

    Cushman, J.R., Cooper, P.N. & Wong, Z.A. (1986c) Modified Buehler
    Test for the skin sensitization potential of RE-45601 Technical
    (SX-1688). Project No. CEHC 2514. Unpublished report dated 15
    December 1986 from Chevron Environmental Health Center Inc.,

    Richmond, CA, USA. Submitted to WHO by Tomen Pacific Agro Co., San
    Francisco, CA, USA.

    Cushman, J.R., Easter, M.D. & Wong, Z.A. (1986d) The acute oral
    toxicity of RE-45601 Technical (SX-1688) in adult male and female
    rats. Project No. SOCAL 2498. Unpublished report dated 27 June 1986
    from Chevron Environmental Health Center Inc., Richmond, CA, USA.
    Submitted to WHO by Tomen Pacific Agro Co., San Francisco, CA, USA.

    Cushman, J.R., Hedgecock, J.H. & Wong, Z.A. (1987a) Four-week
    repeated dose dermal toxicity study in rats with RE-45601 Technical
    (SX-1688). Project No. CEHC 2552. Unpublished report dated 20
    November 1987 from Chevron Environmental Health Center Inc.,
    Richmond, CA, USA. Submitted to WHO by Tomen Pacific Agro Co., San
    Francisco, CA, USA.

    Cushman, J.R., Korenaga, G.L. & Wong, Z.A. (1987b) The acute dermal
    toxicity of RE-45601 Technical (SX-1688) in adult male and female
    rabbits. Project No. CEHC 2510. Unpublished report dated 7 January
    1987 from Chevron Environmental Health Center Inc., Richmond, CA,
    USA. Submitted to WHO by Tomen Pacific Agro Co., San Francisco, CA,
    USA.

    Daly, I.W. & Knezevich, A.L. (1987) Ninety-day subchronic oral
    toxicity study in dogs with Chevron RE-45601 Technical. Project No.
    85-2999. Unpublished report dated 26 February 1987 from Bio/dynamics
    Inc., East Millstone, NJ, USA. Submitted to WHO by Tomen Pacific
    Agro Co., San Francisco, CA, USA.

    Dearlove, G.E., Hoberman, A.M. & Christian, M.S. (1986) Pilot
    teratology study in rabbits with Chevron RE-45601 Technical. Project
    No. 303-007P. Unpublished report dated 15 July 1986 from Argus
    Research Laboratories Inc., Horsham, PA, USA. Submitted to WHO by
    Tomen Pacific Agro Co., San Francisco, CA, USA.

    Dearlove, G.E., Hoberman, A.M. & Christian, M.S. (1987) Teratology
    study in rabbits with Chevron RE-45601 Technical. Project No.
    303-007. Unpublished report dated 30 January 1987 from Argus
    Research Laboratories Inc., Horsham, PA, USA. Submitted to WHO by
    Tomen Pacific Agro Co., San Francisco, CA, USA.

    Dougherty, K.K., Eisenlord, G.H., Low, S.S. & Wong, Z.A. (1987)
    13-Week oral toxicity study in rats with RE-45601 Technical
    (SX-1688). Project No. SOCAL 2501. Unpublished report dated 13
    February 1987 from Chevron Environmental Health Center Inc.,
    Richmond, CA, USA. Submitted to WHO by Tomen Pacific Agro Co., San
    Francisco, CA, USA.

    Dougherty, K.K., Eisenlord, G.H. & Wong, Z.A. (1988a) Combined
    chronic toxicity/oncogenicity study in rats with RE-45601 Technical
    (SX-1688). Project No. SOCAL 2500. Unpublished report dated 1

    November 1988 from Chevron Environmental Health Center Inc.,
    Richmond, CA, USA. Submitted to WHO by Tomen Pacific Agro Co., San
    Francisco, CA, USA.

    Dougherty, K.K., Duncan, R.A. & Wong, Z.A. (1988b) The comparative
    acute oral toxicity of RE-47719 (SX-1800) and RE-45601 (SX-1688) in
    adult female rats. Project No. 2952. Unpublished report dated 21
    October 1988 from Chevron Environmental Health Center Inc.,
    Richmond, CA, USA. Submitted to WHO by Tomen Pacific Agro Co., San
    Francisco, CA, USA.

    Dougherty, K.K., Duncan, R.A. & Wong, Z.A. (1988c) The comparative
    acute oral toxicity of RE-51228 (SX-1796) and RE-45601 (SX-1688) in
    adult female rats. Project No. 2951. Unpublished report dated 21
    October 1988 from Chevron Environmental Health Center Inc.,
    Richmond, CA, USA. Submitted to WHO by Tomen Pacific Agro Co., San
    Francisco, CA, USA.

    Dougherty, K.K., Waid, L.J. & Wong, Z.A. (1989) The acute oral
    toxicity of RE-45601 Technical (SX-1688) in adult male and female
    rabbits. Project No. CEHC 2992. Unpublished report dated 21 June
    1989 from Chevron Environmental Health Center Inc., Richmond, CA,
    USA. Submitted to WHO by Tomen Pacific Agro Co., San Francisco, CA,
    USA.

    Griffis, L.C., Bruce, E.D. & Wong, Z.A. (1986) The acute inhalation
    toxicity of RE-45601 Technical (SX-1688) in rats. Project No. CEHC
    2513. Unpublished report dated 7 November 1986 from Chevron
    Environmental Health Center Inc., Richmond, CA, USA. Submitted to
    WHO by Tomen Pacific Agro Co., San Francisco, CA, USA.

    Hoberman, A.M. & Christian, M.S. (1988a) Oral teratogenicity and
    developmental toxicity screen in rats with RE-47719. Project No.
    303-012. Unpublished report dated 8 November 1988 from Argus
    Research Laboratories Inc., Horsham, PA, USA. Submitted to WHO by
    Tomen Pacific Agro Co., San Francisco, CA, USA.

    Hoberman, A.M. & Christian, M.S. (1988b) Oral teratogenicity and
    developmental toxicity screen in rats with RE-51228. Project No.
    303-010. Unpublished report dated 8 November 1988 from Argus
    Research Laboratories Inc., Horsham, PA, USA. Submitted to WHO by
    Tomen Pacific Agro Co., San Francisco, CA, USA.

    Lee, S.G., Maier, K.M., Tamichi, E.H. & Tucker, B.V. (1988)
    [Ring-4,6-14C] clethodim: A radiocarbon metabolism study in laying
    hens. Project No. MEF-0089. Unpublished report dated 30 December
    1988 from Chevron Chemical Company, Ortho Agricultural Chemicals
    Division, Richmond, CA, USA. Submitted to WHO by Tomen Pacific Agro
    Co., San Francisco, CA, USA.

    Machado, M.L., Lubeck, S.G. & Wilkenfeld, R.M. (1990)
    Microbial/microsome reverse mutation plate incorporation assay with
    RE-45601 Technical (SX-1845). Project No. CEHC 3146. Unpublished
    report dated 20 August 1990 from Chevron Environmental Health Center
    Inc., Richmond, CA, USA. Submitted to WHO by Tomen Pacific Agro Co.,
    San Francisco, CA, USA.

    McKensie, K.M. (1986) Pilot rat reproduction study with Chevron
    RE-45601 Technical. Project No. 6183-102. Unpublished report dated
    16 December 1986 from Hazelton Laboratories America Inc., Madison,
    WI, USA. Submitted to WHO by Tomen Pacific Agro Co., San Francisco,
    CA, USA.

    Mirsalis, J.C. & Steinmetz, K.L. (1986)  In vivo--in vitro
    hepatocyte DNA repair assay:  in vitro evaluation of unscheduled
    DNA synthesis (UDS) following oral administration of Chevron
    RE-45601 Technical to B6C3F1 Mice. Project No. LSC-1960.
    Unpublished report dated August 1986 from SRI International, Meno
    Park, CA, USA. Submitted to WHO by Tomen Pacific Agro Co., San
    Francisco, CA, USA.

    Putnam, D.L. (1986a) Chromosome aberrations in Chinese hamster ovary
    (CHO) cells with Chevron RE-45601 Technical. Project No. T4529.337.
    Unpublished report dated August 1986 from Microbiological Associates
    Inc., Bethesda, MD, USA. Submitted to WHO by Tomen Pacific Agro Co.,
    San Francisco, CA, USA.

    Putnam, D.L. (1986b) Chromosome aberrations in Chinese hamster ovary
    (CHO) cells with purified Chevron RE-45601. Project No. T429.337.
    Unpublished report dated 15 December 1986 from Microbiological
    Associates Inc., Bethesda, MD, USA. Submitted to WHO by Tomen
    Pacific Agro Co., San Francisco, CA, USA.

    Putnam, D.L. (1987) Cytogenetics assay in bone marrow cells of rats
    following acute oral exposure to RE-45601 Technical. Project No.
    T5172.105. Unpublished report dated 25 February 1987 from
    Microbiological Associates Inc., Bethesda, MD, USA. Submitted to WHO
    by Tomen Pacific Agro Co., San Francisco, CA, USA.

    Putnam, D.L. (1988a) Chromosome aberrations in Chinese hamster ovary
    (CHO) cells: RE-47719. Project No. T8226.337003. Unpublished report
    dated 10 November 1988 from Microbiological Associates Inc.,
    Bethesda, MD, USA. Submitted to WHO by Tomen Pacific Agro Co., San
    Francisco, CA, USA.

    Putnam, D.L. (1988b) Chromosome aberrations in Chinese hamster ovary
    (CHO) cells: RE-51228. Project No. T8227.337003. Unpublished report
    dated 10 November 1988 from Microbiological Associates Inc.,
    Bethesda, MD, USA. Submitted to WHO by Tomen Pacific Agro Co., San
    Francisco, CA, USA.

    Rendina, A.R. & Felts, J.M. (1988) Cyclohexanedione herbicides are
    selective and potent inhibitors of acetyl-CoA carboxylase from
    grasses.  Plant Physiol., 86, 983-986.

    Rose, A.F., Griffis, L.C., Suzuki, J.P., Bruce, E.D., Primer, R.L.,
    Wong, Z.A. & Tucker, B.V. (1988a) The  in vivo metabolism of
    [propyl-1-14C] clethodim in rats. Project No. MEF-0086/CEHC 2515.
    Unpublished report dated 22 December 1988 from Chevron Chemical Co.,
    Ortho Agricultural Chemicals Division, Richmond, CA, USA. Submitted
    to WHO by Tomen Pacific Agro Co., San Francisco, CA, USA.

    Rose, A.F., Suzuki, J.P., Primer, R.L. & Tucker, B.V. (1988b) The
     in vivo metabolism of [propyl-1-14C] clethodim in a lactating
    goat. Project No. MEF-0038. Unpublished report dated 29 December
    1988 from Chevron Chemical Co., Ortho Agricultural Chemicals
    Division, Richmond, CA, USA. Submitted to WHO by Tomen Pacific Agro
    Co., San Francisco, CA, USA.

    Schroeder, R.E. & Daly, I.W. (1986) A pilot teratology study in rats
    with Chevron RE-45601 Technical. Project No. 85-3032. Unpublished
    report dated 8 September 1986 from Bio/dynamics Inc., East
    Millstone, NJ, USA. Submitted to WHO by Tomen Pacific Agro Co., San
    Francisco, CA, USA.

    Schroeder, R.E. & Daly, I.W. (1987) Teratology study in rats with
    Chevron RE-45601 Technical. Project No. 86-3042. Unpublished report
    dated 20 July 1987 from Bio/dynamics Inc., East Millstone, NJ, USA.
    Submitted to WHO by Tomen Pacific Agro Co., San Francisco, CA, USA.

    Tellone, C.I., Hardy, L.M. & Richter, W.R. (1987) Two-generation
    (one litter) reproduction study in rats with RE-45601 Technical.
    Project No. CEHC 2596. Unpublished report dated 27 August 1987 from
    Chevron Environmental Health Center Inc., Richmond, CA, USA.
    Submitted to WHO by Tomen Pacific Agro Co., San Francisco, CA, USA.


    See Also:
       Toxicological Abbreviations