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    PHOSALONE

    First draft prepared by
    T.C. Marrs
    Department of Health, London, United Kingdom

    EXPLANATION

         Phosalone was previously evaluated by the Joint Meeting in
    1972, when an ADI of 0-0.006 mg/kg bw was allocated (Annex I,
    reference 18).  This monograph summarizes new or not previously
    reviewed data on phosalone, as well as relevant data from the
    previous monograph that was published on this pesticide.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

    Mice

         Unlabelled phosalone (50 mg/kg bw) orally administered to mice
    disappeared rapidly from the plasma, 7% remaining after 8 hours and
    < 1% after 24 hours (Desmoras & Fournel, 1968).

    Rats

         Male and female Sprague-Dawley rats (Crl:CD(SD)BR) were dosed
    by gavage with 14C ring-labelled phosalone in PEG 200.  Single
    doses of 1 mg/kg bw or 50 mg/kg bw were used.  Muscle tremor, poor
    coordination and lethargy were seen at the high dose.  At the low
    dose, peak blood radioactivity occurred at 1 hour in males and 0.5-2
    hours in females. Excretion of label in the urine and faeces was
    rapid and recovery after 72 hours was 102.3% and 101.3% for males
    and females, respectively.  Almost all the label was excreted in 24
    hours.  Total urinary excretion after 72 hours was 67.6% and 66.3%,
    while total faecal excretion was 21.7% and 18.5% in males and
    females, respectively.  The remainder was found in cage washings. 
    Maximum tissue concentrations occurred 0.5 hours after dosing.  Pre-
    treatment with phosalone for 14 days made very little difference
    (total urinary excretion over 72 hours was 69.5% in males and 66.3%
    in females while faecal excretion was 18.4% and 15.3%,
    respectively); tissue concentrations were marginally increased.  At
    the higher dose, peak blood concentration of label was delayed and
    variable (3-6 hours) in males; 2 peaks occurred in females at 3 and
    24 hours.  About 95% and 94% of the label was recovered in 72 hours
    for males and females, respectively (65.3% and 61.9% for males and
    females in the urine, and 22.6% and 20.8% for males and females in
    the faeces, the remainder being found in cage washings).  In males,
    the vast majority of label was excreted within 24 hours, but in
    females urinary elimination was delayed, 39.6% being excreted in the
    urine in the first 24 hours and 21.8% in the next 24 hours.  Peak
    tissue concentrations were seen at 1.25 and 5 hours in males and 3
    and 9 hours in females; highest concentrations being found in the
    gastrointestinal tract (Hopkins  et al., 1991).

    Cows

         14C-Ring-labelled phosalone was given intraruminally to a
    lactating Holstein cow with an external ruminal fistula.  The label
    was absorbed and eliminated rapidly, 79% being recovered within 48

    hours. After 100 hours, 94% was recovered in the urine, 6.1% in the
    faeces and 0.3% in milk (Craine, 1974a).  In a second study, the
    same author used labelled phosalone of greater purity and higher
    specific activity and a different cow (Craine, 1974b).  The results
    were similar to the earlier study.

    Pigs and rabbits

         14C-Ring-labelled phosalone was poorly absorbed from the skin
    of a pig, 73.5% still being present on the surface of the skin after
    48 hours (Craine, 1974c).  However, Safonov (1968) reported the
    material to be well absorbed from the skin of depilated rabbits.

    Biotransformation

    Mice

         After oral administration to mice, the sulfoxide and sulfone
    were observed in tissues, while phosphorothioates and the sulfoxide
    were seen in the excreta: phosalone oxon was not observed (Desmoras
    & Fournel, 1968; Desmoras, 1979).

    Rats

         Phosalone was extensively metabolized in the rat, the
    metabolites being mainly excreted in the urine.  Many were not
    identified, although small amounts of the sulfoxide and sulfone were
    found.  The main radioactive component found in faeces was
    phosalone.  Tissues such as brain, liver, fat and skeletal muscle
    contained high proportions of the sulfoxide, together with the
    sulfide, sulfone and unchanged phosalone (Hopkins  et al., 1991).
    The putative intermediate, the mercapto compound 2-oxo 3-
    mercaptomethyl 6-chlorobenzoxazole, was not identified in rats. 
    These results are consistent with earlier studies of Desmoras &
    Fournel (1968) and Desmoras (1979) using non-radioactive oral
    phosalone.  In the latter study, the sulfone and sulfoxide were
    observed but not the oxon.

         The putative pathway for metabolism in the rat is presumably
    hydrolysis to O,O-diethylphosphorodithioate and the mercapto
    compound 3-thiomethyl 6-chlorobenzoxazolone, which has not been
    identified  in vivo.  This is subsequently converted to the
    sulfide, which is oxidized to the sulfoxide and to the sulfone
    (Figure 1).

         Studies  in vivo and  in vitro of the formation of the oxon
    of phosalone were carried out in rats.  Small quantities of the oxon
    were formed in the liver.  Moreover, studies using human serum  in
     vitro showed that the addition of guinea-pig liver slices,

    considerably increased the anticholinesterase activity of phosalone
    (Dubost  et al., 1963).  Hence a further mammalian metabolic
    pathway is likely to be hepatic desulfuration of phosalone to
    phosalone-oxon and hydrolysis of the oxon to O,O-
    diethylphosphorothioate.  The other product of hydrolysis would be
    the mercapto compound, with subsequent formation of the sulfide,
    sulfoxide and sulfone.

    Rabbits

         In rabbits after percutaneous administration the excreta
    contained phosalone and probably the sulfoxide and sulfone
    (Desmoras, 1979). Metabolic pathways in mice and rabbits are
    therefore similar to those in rats.

    Cows

         In two studies in lactating cows, the major route of
    elimination was the urine (90%) while 6% was excreted in the faeces. 
    Only 0.3% of the label was excreted in the milk. Biotransformation
    was extensive and only 2% of the label was excreted as phosalone or
    its oxon.  Numerous labelled metabolites were detected in the urine. 
    The main metabolic pathway appeared to be hydrolysis to the marcapto
    compound, 2-oxo 3-mercaptomethyl 6-chlorobenzoxazole, which was
    detected despite being unstable, and presumably alkyl phosphates and
    alkyl phosphorothioates (see Figure 2). 2-Oxo 3-mercaptomethyl-6-
    chlorobenzoxazole was converted via a metabolite which could not be
    identified to 2-amino 5-chlorophenol in a reaction involving
    cleavage of the benzoxazole ring.  Less than 10% of the label found
    in the milk was present as phosalone or the oxon.  Numerous
    components were present in the milk, including 2-oxo 3-
    mercaptomethyl-6-chlorobenzoxazole and 2-amino 5-chlorophenol
    (Craine, 1974a,b, 1975).

         Residue studies in dairy cows were supportive of the above
    metabolic scheme (Rhône-Poulenc Inc, 1979, 1980a,b,c).

    Effects on enzymes and other biochemical parameters

         In early studies, phosalone was shown to be a weak
    cholinesterase inhibitor  in vitro (Dubost  et al., 1963; Rhône-
    Poulenc, 1968) and it inhibited rat whole blood cholinesterase  in
     vivo (Dubost  et al., 1963).  In  in vitro systems,
    phosaloneoxon is approximately 1000 times more powerful as an
    anticholinesterase than phosalone (Desmoras & Fournel, 1968).   In
     vivo in rats, orally administered phosalone is 4-9 times less
    effective in inhibiting plasma or red cell cholinesterase than
    phosaloneoxon (Fournel  et al., 1968).  Presumably phosalone exerts
    mammalian anticholinesterase activity only after conversion to its
    oxon, like other phosphorothioates and phosphorodithioates of the
    P=S type (WHO, 1986).  The cholinesterase inhibitory potential of 

    FIGURE 01

    FIGURE 02

    technical grade phosalone is probably due to small amounts of oxon
    present (up to 0.5% of the present technical material).  The reason
    that phosalone oxon did not inhibit rat brain cholinesterase at
    single doses up to 9 mg/kg bw, whereas phosalone did at 27 mg/kg bw
    (surprising in view of the much higher acute toxicity of the former)
    is obscure (Fournel  et al., 1968).  Inhibition of brain
    cholinesterase by phosalone was also observed by Pasquet  et al.
    (1976) with an I50 of 31 mg/kg bw p.o.  Phosalone was reported to
    shift to the right the oxygen dissociation curve in rats (Reddy  et
     al., 1992).

    Toxicological studies

    Acute toxicity studies

         A summary of acute toxicity data for phosalone is shown in
    Table 1.  Phosalone has been classified as moderately hazardous by
    WHO (WHO, 1992).

    Short-term toxicity studies

    Rats

         A dose of 50 mg/kg bw/day administered by gavage (vehicle
    unstated) to white rats for 14 days was lethal (Safonov, 1968).

         Phosalone was administered as an oil solution to male rats
    (10/dose) (strain unstated) at doses of 7.5 or 15 mg/kg bw/day for 5
    weeks.  The only death seen in the study was a control rat and no
    abnormal clinical signs were observed.  Slight reductions in body-
    weight gain noted at both dose levels were not statistically
    significant.  No major differences between test and control groups
    were seen in haematology or clinical chemistry except in
    cholinesterase activity.  Depression of blood cholinesterase
    activity (> 20%) was observed at both doses.  Brain cholinesterase
    activity was reduced at the high dose only.  No statistically
    significant differences in organ weights or pathological findings
    were seen between test groups and controls.  The NOAEL was 7.5 mg/kg
    bw/day, based on brain cholinesterase inhibition (Dubost  et al.,
    1963).

         In an 8-week study, groups of 10 Crl:CD(SD) rats/sex/dose
    received 10, 100, 300, 600 or 1200 ppm phosalone (94.1% pure) in the
    diet.  After 5 weeks, the doses administered to the 100 and 300 ppm
    groups were increased to 2400 and 4800 ppm, respectively, in order
    to establish the maximum tolerated dose.  At 300/4800 ppm, one
    female died and all remainder animals were sacrificed  in extremis. 
    At 100/2400 ppm all females had to be sacrificed. Males at both
    these doses survived but showed reduced body weight and food 


        Table 1.  Acute toxicity of phosalone
                                                                                                  

    Species        Strain              Sex    Route   LD50 (mg/kg bw)     References

                                                                                                  

    Mouse          CD-1(COBS)          M      p.o.    118 (97-144)        Fournel et al. (1968)
    Mouse          CD-1(COBS)          F      p.o.    93 (74-116)         Fournel et al. (1968)
    Mouse          ?                   ?      p.o.    180* 435**          Dubost et al. (1963)
    Mouse          ?                   ?      p.o.    205                 Dubost et al. (1963)
    Mouse          ?                   ?      p.o.    180                 Safonov (1968)
    Rat            ?                   M      p.o.    120                 Dubost et al. (1963)
    Rat            CD(COBS)            M      p.o.    125 (102-152)       Fournel et al. (1968)
    Rat            ?                   F      p.o.    170                 Dubost et al. (1963)
    Rat            ?                   F      p.o.    135                 Dubost et al. (1963)
    Rat            CD(COBS)            F      p.o.    90 (68-119)         Fournel et al. (1968)
    Rat            ?                   ?      p.o.    50                  Hayward (1969)
    Rat            ?                   ?      p.o.    135                 Safonov (1968)
    Rat            CD(COBS)            M      p.o.    130 (104-163)       Pasquet et al. (1976)
    Rat            CD(COBS)            F      p.o.    110 (87-139)        Pasquet et al. (1976)
    Rat            ?                   F      p.c.    390                 Dubost et al. (1963)
    Rat            CD(COBS)            F      p.c.    700 (480-1015)      Pasquet (1971)
    Rat            CD(COBS)            F      p.c.    1530                Mazuret (1971)
    Rat            ?                   F      p.c.    > 2560              Pasquet & Mazuret (1973a)
    Rat            CD(COBS)            F      p.c.    1530                Pasquet et al. (1976)
    Rabbit         ?                   ?      p.c.    > 1000              Dubost et al. (1963)
    Guinea-pig     ?                   ?      p.o.    150                 Dubost et al. (1963)
    Guinea-pig     ?                   ?      p.o.    82                  Dubost et al. (1963)
    Hens           Rhode Island red    F      s.c.    350                 Heath et al (1967)

                                                                                                  

    *    Aqueous Suspension
    **   Oil solution
    

    consumption. Body weight and cumulative body-weight gain were
    significantly lower in females receiving 1200 ppm.  No changes were
    seen in the eyes.  Significantly lower plasma and erythrocyte
    cholinesterase were seen at 100 ppm in both sexes.  Brain
    cholinesterase activity was decreased at 600 ppm to about 80% and
    50% of controls in males and females, respectively.  Other changes
    in clinical chemistry parameters were seen at higher doses,
    including lower blood glucose, total protein and albumen and higher
    cholesterol and blood urea. No treatment-related changes were seen
    in organ weights or in organs on macroscopic or microscopic
    examination. The NOAEL was 10 ppm, equal to 0.87 mg/kg bw/day in
    males and 0.93 mg/kg bw/day in females, based on brain
    cholinesterase inhibition (Kehoe, 1990).

    Rabbits

         A 3-week percutaneous study was undertaken in rabbits using
    phosalone at doses of 0.4, 2.0 or 10 mg/kg bw/day
    acetone/ethanol/arachid oil.  There were no deaths.  A 20%
    depression in brain cholinesterase occurred in the highest dose
    females. Some irritancy was observed (Kynoch  et al., 1979).

    Dogs

         Phosalone was administered orally to dogs in oil solution for 1
    month at dose levels of 7.5, 15 or 30 mg/kg bw/day. One animal of
    each sex was used at each dose without controls. Neither clinical
    signs nor significant weight changes were noted.  Albumen/globulin
    ratios in both animals treated with phosalone at 7.5 mg/kg bw/day
    were depressed; however, this was not seen in the 15 mg/kg bw/day
    animals.  Significant plasma and erythrocyte cholinesterase
    depression were seen in all animals except in females at 7.5 mg/kg
    bw/day.  A NOAEL could be not be determined in this study (Dubost
     et al., 1963).

         In another one-month study, groups of 4 beagle dogs/sex/dose
    were administered phosalone (100% pure) at dietary concentrations of
    0, 12.5, 25 or 37.5 ppm.  No deaths were observed nor were there
    abnormal clinical signs.  There was no adverse effect on body
    weight.  Plasma cholinesterase activity was depressed by > 20% in
    the high-dose group. Erythrocyte and brain cholinesterase activity
    were not affected.  At terminal autopsy a mauve discoloration was
    observed in the bladder of all high- and mid-dose animals and in one
    female at the low dose. Since the bladder discoloration was not seen
    in any other dog study, the NOAEL was the highest dose of 37.5 ppm,
    equal to 0.81 mg/kg bw/day (Noel  et al., 1970).

         In a 6-month study, groups of beagle dogs (4/sex/dose) received
    phosalone at 0, 10 or 25 ppm in the diet.  No haematological,
    biochemical or histological changes attributable to phosalone were

    observed except in erythrocyte and plasma cholinesterase.  Brain
    cholinesterase activity was not depressed.  Depression of plasma
    cholinesterase activity of about 40% and 25% was observed in the 25
    ppm and 10 ppm groups, respectively.  Decreased erythrocyte
    cholinesterase activity was seen only at 25 ppm towards the end of
    the study.  The NOAEL was the highest dose (25 ppm, equivalent to
    0.63 mg/kg bw/day) (Fournel  et al,. 1966).

         In a 107-week study, phosalone (purity unknown) was
    administered in the diet to groups of 4 beagle dogs/sex/dose at
    concentrations of 0, 100, 200 or 1000 ppm.  One female at 1000 ppm
    died during the study.  Although marked plasma and erythrocyte
    cholinesterase depression were observed, the immediate cause of
    death seemed to be an infection.  Body-weight loss was seen at 100
    ppm, and cholinergic symptomatology was seen in two animals at the
    highest dose and in one animal at 100 ppm. Abnormal ECGs (increased
    T-waves) were seen at 1000 ppm.  Biochemical and haematological
    investigations demonstrated no changes that appeared to be compound-
    related apart from elevations in ALAT in 4 animals at 1000 ppm. 
    Reductions in plasma cholinesterase > 20% were observed at 100 ppm
    and above, and in erythrocyte cholinesterase at 200 ppm and above. 
    The degree of brain cholinesterase inhibition was variable, with a
    mean in the 1000 ppm group of 79% of controls.  Inhibition at
    termination of the study was considerable in 3/8 animals and almost
    complete in 2 animals. The NOAEL was 200 ppm, equivalent to 5 mg/kg
    bw/day, based on clinical signs, body-weight loss, elevated ALAT and
    brain cholinesterase depression at 1000 ppm (Donoso  et al., 1967).

         Groups of 6 beagle dogs (6/sex/dose) received 0, 5, 25 or 300
    ppm phosalone (94.5% pure) in the diet for 52 weeks.  Three deaths
    in different groups were observed.  During week 43, all animals
    receiving 300 ppm vomited and lost weight and 5 showed reduced food
    consumption.  Some recovery in weight occurred towards the end of
    the study.  No changes of toxicological importance occurred on
    ophthalmological, haematological, biochemical or urinary examination
    except for cholinesterase activity. Reduction in plasma
    cholinesterase > 20% compared to controls occurred in the 25 and
    300 ppm groups (both sexes and combined and at all time points after
    dosing commenced).  At 5 ppm, significant reductions occurred in
    males only at 4, 26, and 52 weeks.  These reductions were just under
    20%.  Red cell cholinesterase was significantly reduced at 300 ppm
    at all time points.  At 25 ppm, this enzyme was reduced compared to
    the control group in males at 26 weeks and in both sexes at 52
    weeks.  The reduction in this group compared to pre-dosing levels
    was < 15%.  Brain cholinesterase was significantly reduced in both
    sexes at 300 ppm to about 60% of control values.  No significant
    differences between groups were observed in organ weights or after
    macroscopic or histopathological examination of organs. The NOAEL
    was 25 ppm, equal to 0.89 mg/kg bw/day (males) and 0.97 mg/kg bw/day
    (females), based on depression of brain cholinesterase activity and
    clinical effects at 300 ppm (Barker  at al., 1992).

    Long-term toxicity/carcinogenicity studies

    Mice

         In a 2-year study in CD-1 mice (60-65/sex/group), phosalone
    (95.3% pure) was administered at dietary concentrations of 0, 15, 50
    or 150 ppm.  Five mice of each sex were sacrificed at 6 weeks and at
    study termination at 105 weeks for plasma, erythrocyte and brain
    cholinesterase determinations.  Plasma and erythrocyte
    cholinesterase were reduced by at least 20% in the 150 ppm group at
    both 6 and 105 weeks. In some cases, particularly with plasma
    cholinesterase, the reduction was much greater.  Brain
    cholinesterase was not reduced compared to controls.  Statistically
    significant increases in adrenal weights were found at all dose
    levels and in both sexes, with the exception of females at the
    lowest dose.  These increases were both in relative and absolute
    weights and were significant except for relative weight at 15 ppm in
    males.  Decrease in absolute brain weight was significant at 50 ppm
    and 150 ppm in males.  Relative increases in testicular weights (50
    ppm), kidney weights in females only (15 ppm) and relative and
    absolute increases in pituitary weights (males: 15 ppm) were also
    significant. No neoplastic or non-neoplastic histopathological
    findings were attributable to phosalone. There were adrenal weight
    changes, which in the absence of histopathological changes, were
    considered to be adaptive, and changes in testicular weights at 50
    ppm and kidney weight in one sex at 15 ppm which were likely to be
    insignificant in view of a lack of dose-response. The decrease in
    absolute brain weight in males was not dose-related. The NOAEL was
    thus the highest level of 150 ppm (equal to 23 and 31 mg/kg bw/day
    in males and females, respectively), based on the lack of depression
    of brain cholinesterase activity at this level (Nelson  et al.,
    1980).

    Rats

         In a 2-year study, groups of 30 rats/sex/dose (albino: strain
    not stated) received phosalone of unknown purity at dietary
    concentrations of 0, 25, 50 or 250 ppm (half of these concentrations
    for the first four weeks).  Mortality during the course of the study
    was similar in all groups.  There was some depression in weight gain
    in the highest-dose animals compared to controls, especially in
    males at 103 weeks.  No haematological changes attributable to the
    test material were observed.  There were marked (up to three-fold)
    differences in group mean plasma cholinesterase activities between
    sexes, females having much higher activity; this raised some doubt
    about the reliability of these assays.  Inhibition of erythrocyte
    and plasma cholinesterase activity was seen at 250 ppm.  Inhibition
    of brain cholinesterase activity > 20% was seen at 250 ppm in
    males. No histopathological changes related to the test material
    were seen.  Although a few instances of testicular activity were

    seen, there was no indication of any relationship between occurrence
    of this finding and administration of the test material.  The NOAEL
    was 50 ppm, equivalent to 2.5 mg/kg bw/day, based on brain
    cholinesterase inhibition at the next highest dose (Woodard Research
    Corporation, 1967).

         In a second 2-year study, Sprague-Dawley CD rats (50/sex/dose)
    were given phosalone (purity 94.5%) at doses of 0, 5, 50 or 1000
    ppm, the highest dose being reduced to 500 ppm at week 27. These
    concentrations were equal to 0, 0.2, 1.8 or 20 mg/kg bw/day for
    males and 0, 0.2, 2.5 or 31 mg/kg bw/day for females, on the basis
    of consumption data from week 27.  Satellite groups of animals
    (15/sex/dose), were killed at 52 weeks. There was no effect on
    mortality and clinical effects were mainly confined to the high-dose
    group. Depression of plasma and erythrocyte cholinesterase was found
    at the high and medium concentrations and depression of brain
    cholinesterase activity was found in the highest dose group. There
    were some treatment-related changes in the adrenals. A dose-response
    across all groups in the prevalence of testicular atrophy was
    observed (1/27, 3/34, 6/30 10/42 in survivors to the terminal kill). 
    Reductions in testis weight were dose-related, but were
    statistically significant only at the high and mid-dose levels (5.03
    g, 4.66 g, 4.51 g and 4.22 g, for the control, low, medium and high-
    dose groups, respectively).  The NOAEL was < 5 ppm, equal to 0.2
    mg/kg bw/day (Barker & Sortwell, 1993).

    Reproduction studies

    Rats

         In a three-generation reproduction study, groups of albino rats
    (10 males and 20 females/group) were administered phosalone (purity
    unknown) at dietary concentrations of 0, 25 or 50 ppm.  Only half
    the nominal dietary concentration was given during the initial three
    weeks of the diet, on the grounds that young rats eat about twice as
    much daily during this period; this procedure was repeated in each
    generation.  When the rats had received phosalone for 74 days, 10
    females in each group were paired with the 10 males from the same
    group for 10 days, after which the other 10 females were mated with
    the 10 males.  The animals from these litters (F1a) were sacrificed
    after weaning, weighed and examined. Microscopic histopathological
    examination was not carried out.  The F0 rats were then remated as
    different pairs to produce the F1b litters.  Litters were examined
    at weaning and representative male and female pups were placed on
    control diet to constitute the next study groups.  Within 21 days of
    weaning, the F1b generation received 25 ppm or 50 ppm phosalone,
    while controls continued to be fed control diet.  The F1b rats were
    mated in the same way as the F0 generation, F2a pups being
    sacrificed and examined as above, while the F1b parents were also
    killed and examined.  Uteruses from females failing to bear two

    litters were removed and examined for implantation sites.  Rats were
    selected from each F2b litter to give 10 males and 20 females in
    each group, the remaining F2b pups were sacrificed and examined as
    before without microscopic pathology.  The retained F2b pups in the
    two test groups received the test diet within 24 days of weaning. 
    After 51 days on the diet, the males and 10 females were paired for
    10 days, the males being paired with the other 10 females after they
    had all been on the diet for 71 days.  The F3a pups were sacrificed
    after weaning and examined as above.  Within 10 days, F2b females
    were re-mated with different males to produce the F3b litters.
    After weaning, the pups were sacrificed and the main organs
    examined. Tissues from one male and one female in each F3b litter
    were examined histopathologically.  The F2b parents were mated for
    a third time to produce F3c pups litters, which were treated in the
    same way as the F3b pups.

         The test groups of rats were similar to the controls throughout
    the study.  Three F0 females died in the 50 ppm group and one in
    the 25 ppm group while none died in the control group.  Test
    substance-related effects on fetal resorption were not observed and
    malformations were observed only in 3 pups from one litter of the 25
    ppm group.  The three pups exhibited flaccid paralysis of the hind
    limbs.  Organs from the test and control weanlings from the F3b and
    F3c groups did not differ significantly in weight or
    histopathology.  No adverse effect was determined in the study and
    the NOAEL was > 50 ppm, equivalent to 2.5 mg/kg bw/day (Jones  et
     al., 1967a).

         In a two-generation reproduction study, groups of 32 male and
    32 female rats (6 week-old Crl: CD(SD)VSAF/Plus BR) were given
    phosalone (96.8% pure) at dietary concentrations of 0, 10, 50 or 400
    ppm. Phosalone was administered for 10 weeks, after which the rats
    were mated for 20 days.  The dams were allowed to rear their young
    and from these litters, 21 days postpartum, 28 rats/sex/group were
    selected as the F1 generation.  F1 animals were selected and
    treated from weaning until 16 weeks when they were mated.  After
    weaning of their litters the F1 parents were sacrificed as were the
    F2 pups.

         At 400 ppm, there was a lower body weight from conception to
    day 17 in the F0 generation, and lower mean body-weights of the F1
    males and females.  There were 2 total litter losses post-partum in
    the F0 generation and three in the F1 generation.  There was a
    reduced litter size in the F0 animals and increased pup mortality
    to day 4 in both generations.  Retarded pup growth and marked plasma
    and erythrocyte cholinesterase depression were noted in both
    generations.  At 50 ppm, there was marked plasma and erythrocyte
    cholinesterase depression in both generations, while at 10 ppm
    cholinesterase reduction was < 20%.  Brain cholinesterase activity 

    was not measured.  The NOAEL was 50 ppm, equivalent to 2.5 mg/kg
    bw/day, based on retarded pup growth and erythrocyte cholinesterase
    depression (Bryson  et al., 1991).

    Special studies on embryotoxicity/teratogenicity

         A study was carried out on chick embryos (white Leghorn) at
    doses of 0.2, 0.6 or 1.8 mg/egg, using 30 eggs/group.  Two further
    groups of 30 eggs served as solvent (dimethylsulfoxide) and
    untreated controls.  At 18 days, the surviving embryos were removed,
    weighed and examined.  Phosalone had no significant effect on
    mortality, weight or structure (Pasquet, 1969).

         Groups of 25 female rats (Wistar HAN) were treated with 0, 2,
    10 or 20 mg/kg bw/day of phosalone by gavage, from days 6 through 15
    of gestation.  Controls received distilled water with 4% CMC.  The
    animals were killed 21 days after coitus and the fetuses were
    removed by caesarean section. Dams and fetuses were examined
    macroscopically and microscopically.  Oral administration of
    phosalone at the highest dose produced clinical signs (chewing
    movements, piloerection and dyspnea).  Additionally, reduced food
    consumption, weight loss, reduction in litter size, due to increased
    resorptions and a slight increase in mean fetal body weight, were
    observed.  There was no evidence of fetal abnormality.  At 2 and 10
    mg/kg bw/day, maternal and fetal parameters were similar to
    controls.  The NOAEL was 10 mg/kg bw/day for both maternal toxicity
    and fetotoxicity (Allen  et al., 1989a).

         Groups of 25 Fauve de Bourgogne rabbits were orally treated by
    capsules with undiluted phosalone (purity unstated) from days 6
    through 16 of gestation with doses of 0, 2, 6 or 18 mg/kg bw/day.  A
    positive control group was treated with thalidomide. The does were
    sacrificed at 28 days.  The percentage of animals becoming pregnant,
    the number of resorptions, the number of fetuses recovered alive
    after caesarian section and their weight did not differ
    significantly from the untreated controls.  The incidence of
    malformed fetuses was low in all groups and the malformations were
    trivial.  By contrast malformations were observed in the thalidomide
    group.  The NOAEL was 18 mg/kg bw/day, the highest dose tested
    (Pasquet, 1969).

         Phosalone (93.5% pure) was administered in
    carboxymethylcellulose (4%) by gavage to Chinchilla KFM/CHIN rabbits
    (16/dose) at doses of 0, 1, 10 or 20 mg/kg bw/day from days 6
    through 18 post-coitum.  Clinical signs of cholinergic intoxication,
    particularly dyspnea and extensor spasms, reduced food consumption,
    loss of body weight and increased incidence of resorption of embryos
    were observed at the highest dose.  Post-implantation loss was
    increased at 10 and 20 mg/kg bw/day compared to concurrent controls
    but was within the range of historical controls.  No adverse effect

    was seen on fetuses at any dose, or on maternal parameters at doses
    of 1 or 10 mg/kg bw/day.  The NOAEL was 10 mg/kg bw/day, based on
    both fetal and maternal toxicity (Allen  et al., 1989b; Allen,
    1989).

    Special studies on genotoxicity

         Based on the results of genotoxicity assays given in Table 2,
    the Meeting concluded that phosalone was not genotoxic. 

    Special studies on neurotoxicity

         Groups of white Leghorn hens (10/group/dose) were given dietary
    doses of 0, 50, 163 or 500 ppm phosalone or TOCP at 500 ppm for 45
    days.  Hens were examined daily during the study.  At termination,
    brain, three levels of spinal cord and a portion of sciatic nerve
    were taken from the controls, the TOCP-treated birds and the highest
    dose of phosalone-treated hens.  Although some signs of cholinergic
    toxicity occurred, no phosalone-treated birds showed any indication
    of organophosphate-induced delayed neuropathy.  TOCP-treated hens
    showed paralysis from 13 days onwards, and the only deaths seen,
    were amongst the TOCP-treated fowl.  Histopathological appearances
    in tissues taken from the control and phosalone-treated animals were
    within normal limits.  Although there was some demyelination in the
    TOCP group of animals, particularly in the sciatic nerve, this was
    not significant (Woodard  et al., 1966).

         In another study, 10 Rhode Island red hens were dosed with 350
    mg/kg bw phosalone (=LD50) as a 35% formulation, while protected by
    atropine and pralidoxime methanesulfonate (P2S).  The dose was
    repeated after 3 weeks.  There were 4 untreated controls and 4
    positive controls treated with a neuropathic dose of mipafox.  One
    phosalone-treated hen died at 4 days, and another at 29 days.  No
    pathological changes were seen in the spinal cord.  The positive
    controls became severely ataxic at 13 days and showed serious
    effects in the spinal cord.  The untreated controls were clinically
    and pathologically normal (Heath  et al., 1967). 

         Groups of 20 New Hampshire red hens received TOCP (750 mg/kg bw
    p.o., positive control), or 0 or 600 mg/kg bw p.o., phosalone. 
    Dosed and positive control animals also received atropine 15 min
    before dosing.  The vehicle control and phosalone group were redosed
    at day 22 and sacrificed at day 41.  Birds from the first positive
    control group were killed on day 22 of the study at which time the
    10 birds from the second positive control group were dosed and
    sacrificed 19 days later.  No significant clinical signs were seen
    in the vehicle control fowl.  Neuropathological examination was
    performed on central and peripheral nervous tissue from all terminal
    sacrificed animals and seven decedents in the phosalone group.  


        Table 2.  Results of genotoxicity assays on phosalone
                                                                                                                               
    Test                Object                     Concentration phosalone     Purity      Results      Reference
                                                                                                                               
    In vitro 

    Ames test (1)       S. typhimurium             1-1000 µg/plate             ?           Negative     Benezet & Cartier, 1980
                        (strains TA98, 100,        125-1000 µg/plate
                        1535, 1537)

    Ames test (1)       S. typhimurium             250-10 000                  94%         Negative     Haworth & Lawlor, 1989
                        (strains TA98, 100,        µg/plate
                        1535, 1537, 1538)

    HPRT test (1)       CHO/K1 cells               0.1-50 µg/ml                95%         Negative     Cordier & Bonneau, 1985

    Chromosomal         CHO/K1 cells               4, 40, 75 µg/ml             95%         Negative     Cordier & Fournier, 1989
    aberration in 
    CHO cells (1)

    Chromosomal         CHO/WBL cells              16.7, 500 µg/ml             94%         Negative     Murli, 1989
    aberration in                                  (also 5 µg/ml without 
    CHO cells (1)                                  metabolic activation)

    UDS in vitro        Rat primary                0.005-252 µg/ml             94%         weak         Cifone, 1989
                        hepatocyte                                                         positive

    In vivo

    Micronucleus        CD-1 mice                  10, 20, 40 mg/kg bw/day     99.5%       Negative     Pasquet & Fournier, 1980

    Dominant lethal     CD-1 mice                  10, 30, 75 mg/kg            95.3%       Negative     Goldenthal et al., 
    test                                                                                                1978
                                                                                                                               

    (1)  With and without metabolic activation.
    

    Tissues examined were spinal cord (cervical, thoracic and
    lumbosacral), medulla, sciatic and tibial nerves.  In the positive
    control groups, all except one bird showed clinical signs of delayed
    neuropathy, appearing from days 13-24.  In both positive controls,
    histopathological evidence of delayed neuropathy was found.  In the
    phosalone group, 4 birds showed signs of cholinergic toxicity after
    the first dose and two birds died.  On day 22 after the second dose,
    six hens showed acute toxicity.  Seven hens died on days 23-24. 
    Histopathological evidence of nerve degeneration was not more
    frequent in this group than in the vehicle controls (Morris, 1983).

         The Meeting concluded that there is no evidence that phosalone
    has potential to cause organophosphate-induced delayed neuropathy.

    Antidote studies of phosalone intoxication

         Ten groups of 10 mice each were given phosalone orally followed
    immediately by i.p. administration of combinations of pralidoxime
    methylsulfate (Contrathion) at 0, 25, 50, 100 or 200 mg/kg bw and
    atropine at 0, 10, 20 or 40 mg/kg bw.  Both antidotes were effective
    in preventing death although pralidoxime methylsulfate at 100 and
    200 mg/kg bw appeared to be toxic.  Some aspects of the results were
    difficult to interpret since doses of pralidoxime methylsulfate used
    were high compared to the recommended human dose of 5-6 mg/kg bw
    (SERB, 1988).  Moreover the i.p. LD50 of a similar pralidoxime salt
    is 125-250 mg/kg bw in the mouse (Marrs, 1991).  Doses of atropine
    used in this study were also high (Dubost  et al., 1963).

         In another study using orally administered phosalone (vehicle
    unstated), groups of rats (9-10/group) were given 50 or 100 mg/kg bw
    phosalone. Phosalone (100 mg/kg bw) was administered to another
    group of 10 rats, followed by pralidoxime methanesulfonate (50 mg/kg
    bw s.c.) and atropine (17.5 mg/kg bw s.c.) 15-20 minutes after
    clinical signs of anticholinesterase poisoning developed.  All
    animals in the 100 mg/kg bw group not treated with the antidotes
    showed considerably reduced erythrocyte anticholinesterase activity
    and died within 24 hours.  Five out of 10 rats survived 24 hours in
    the 50 mg/kg bw group and their cholinesterase activity was less
    depressed.  When treated with the antidotal regime, 9/10 rats dosed
    with phosalone at 100 mg/kg bw survived and cholinesterase activity
    was less depressed than that of animals treated with 50 mg/kg bw
    phosalone but untreated with antidotes (Hayward, 1969).

         In a study of the antidotal effects of bis-pyridinium oxime
    (obidoxime), groups of mice (4/sex) were administered phosalone by
    gavage at a dose of 250 mg/kg bw, a dose well above the LD50. 
    Immediately afterwards, obidoxime and atropine were injected
    intraperitoneally at obidoxime doses of 0, 25, 50 or 100 mg/kg bw
    and at atropine doses of 0, 10, 20 or 40 mg/kg bw in various
    combinations.  When no antidote was given, phosalone was invariably

    fatal whereas survival was considerably improved with combinations
    of antidote except at the highest dose of atropine and obidoxime. 
    Obidoxime alone was clearly more beneficial than atropine alone. 
    Synergism was not observed, because of the study design (Pasquet &
    Masuret, 1970).

         It was concluded from these studies that atropine is an
    effective antidote to phosalone.  Pralidoxime (either methylsulfate
    or methanesulfonate) reactivated phosalone-inhibited rat erythrocyte
    cholinesterase and was an effective antidote.  Obidoxime was also an
    effective antidote but the usual synergism of atropine and
    pralidoxime salts or obidoxime was not noted probably due to the
    design of the studies.

    Special studies on metabolites and intermediates

         A number of acute toxicity and genotoxicity studies have been
    conducted with phosalone metabolites and intermediates.  The results
    are summarized in Tables 3-6.

    Other studies

         3-Hydroxymethyl 6-chlorobenzoxolone was non-irritant to the
    intact rabbit skin but very irritant to the scarified skin (Pasquet
    & Mazuret, 1973b). 3-Chloromethyl 6-chlorobenzoxolone was non-
    irritant to the intact rabbit skin (Pasquet  et al., 1983b).

         In a 13-week study, groups of 15 male and 15 female rats
    (Sprague-Dawley-derived Crl:CD(SD)BR) were given 6-chlorobenzoxolone
    at dietary concentrations of 0,5, 15 or 45 mg/kg bw/day for 13
    weeks.  Groups of 10 male and female controls and high-dose animals
    underwent a subsequent 28-day treatment-free period.  The only
    effect of the treatment was suppression of weight gain in all
    treated males and in the high-dose females.  A compensatory weight
    gain was observed in the animals that underwent the treatment-free
    period (Owens, 1985).

         A study was performed to determine the potential of Di-syston
    (disulfoton) to potentiate the activity of phosalone.  Groups of 8
    beagle dogs were fed diets containing phosalone at concentrations of
    7.5, 15 or 25 ppm for 19 weeks.  In each case, Di-syston was added
    at a concentration of 1 ppm from week 14 to week 19.  There were no
    changes in physical appearance, haematology or pathology that could
    be ascribed to the treatment.  No treatment-related changes in
    plasma or erythrocyte cholinesterase were seen (Jones  et al.,
    1967b).


        Table 3.  Acute toxicity of phosalone metabolites
                                                                                            
    Species     Strain            Sex      Route       LD50          References
                                                     (mg/kg bw)
                                                                                            

    Phosalone-oxon

    Mouse       CD-1(COBS)        M        PO            35          Fournel et al., 1968
                                                       (30-41)
    Mouse       CD-1(COBS)        F        PO            40          Fournel et al., 1968
                                                       (33-49)
    Mouse       ?                 Mix      PO            32          Rhône-Poulenc, 1968

    Rat         CD(COBS)          M        PO            36          Fournel et al., 1968
                                                       (29-44)
    Rat         CD(COBS)          F        PO            21          Pasquet et al., 1976
                                                       (12-28)
    Rat         CD(COBS)          F        PO            20          Fournel et al., 1968
                                                       (15-29)
    Rat         CD(COBS)          F        PC            380         Pasquet & Mazuret, 1973a
                                                      (240-610)

    3-methylthiomethyl 6-chlorobenzoxazolone

    Mouse       OF1               M        PO            590         Pasquet & Mazuret, 1980
                                                      (499-698)
                OF1               F        PO            837         Pasquet & Mazuret, 1980
                                                      (706-991)

    3-methylsulfinylmethyl 6-chlorobenzoxazolone

    Mouse       OF1               M        PO            405         Pasquet & Mazuret (1980)
                OF1               F        PO            315         Pasquet & Mazuret (1980)
                                                      (256-386)

                                                                                            

    Table 3 (contd)
                                                                                            
    Species     Strain            Sex      Route       LD50          References
                                                     (mg/kg bw)
                                                                                            

    3-methylsulfonylmethyl 6-chlorobenzoxazolone 

    Mouse       OF1               M        PO          > 5000        Pasquet & Mazuret 1980
                OF1               F        PO          > 5000        Pasquet & Mazuret 1980

                                                                                            


    Table 4.  Acute toxicity of intermediates and soil metabolites
                                                                                            
    Species     Strain            Sex      Route       LD50          References
                                                     (mg/kg bw)
                                                                                            

    3-hydroxymethyl 6-chlorobenzoxolone 

    Mouse       CD-1(COBS)        Mix      p.o.          730         Pasquet & Mazuret, 1973b
                                                      (557-956)
    Benzoxolone

    Mouse       CD-1(COBS)        Mix      p.o.          580         Pasquet & Mazuret, 1973b

    3-chloromethyl 6-chlorobenzoxolone 

    Rat         CD Sprague-       Mix      i.p.          305         Pasquet et al., 1983a
                Dawley

                                                                                            

    Table 5.  Genotoxicity of phosalone intermediates
                                                                                                                
    Compound          Test object                Concentration            Purity    Result    References
                                                 intermediate
                                                                                                                

    Unknown intermediate

    Ames test (1)     Salmonella typhimurium     0.005-0.5 µg/plate       ?         -ve       Weill, 1988
                      TA98, TA100, TA1535, 
                      TA1537, TA1538

                                                                                                                


    Table 6.  Genotoxicity of phosalone soil metabolites
                                                                                                                
    Compound          Test object                Concentration            Purity    Result    Reference
                                                 intermediate
                                                                                                                

    3-amino 7-chloro 2-phenoxazone

    Ames test (1,2)   Salmonella typhimurium     10-100 µg/plate (-S9)    95%       +ve       Vanrel et al., 1989
                      TA98, TA100. TA1535,       25-125 µg/plate (+S9)                        
                      TA1537, TA1538                                                          

                                                                                                                

    (1)  With and without metabolic activation.
    (2)  Positive with metabolic activation and in TA1537, and TA100 only.
    

         Phosalone (96% pure) was applied to the skin of rabbits (New
    Zeeland white) for 21 days at dose levels of 0.4, 2 or 10 mg/kg
    bw/day.  Azinphosethyl was applied at 2 mg/kg bw/day.  Both
    chemicals were applied to intact or abraded skin.  Inhibition of
    brain cholinesterase > 20% was not noted in any phosalone group,
    but marked depression was seen with azinphosethyl.  Phosalone did
    not cause red blood cell or plasma cholinesterase depression (Kynoch
     et al., 1979).

         In studies to elicit delayed sensitization in guinea-pigs
    (Pasquet & Mazuret, 1977; Cunny & Siglin, 1989) no sensitization was
    seen.  Phosalone was moderately irritant to the eye in New Zeeland
    white rabbits (Siglin  et al., 1989).  Irritancy to the rabbit eye
    was also observed by Safonov (1968).

    Observations in humans

         In a study performed on 14 male volunteers to establish a re-
    entry period after applying phosalone in citrus groves, dislodgeable
    residues up to 3.6 µg/cm2 (leaf) produced no adverse effect other
    than some plasma cholinesterase depression (Knaak  et al., 1978).

         In 1987, several cases of illness resembling anticholinesterase
    poisoning were reported in California.  On investigation by the
    California Department of Food and Agriculture, it was found that the
    illness had occurred in workers harvesting grapes from vineyards
    treated with a preparation containing phosalone.  A study was
    therefore carried out in which grapes were treated with phosalone (3
    lb/acre) twice, 24 days apart.  Fourteen days after the second
    treatment, 30 volunteers harvested the crop for 6 consecutive days
    while 22 volunteers harvested a crop from an untreated vineyard. 
    Assignment to the treated or control group was random.  Blood was
    collected for plasma and erythrocyte cholinesterase activity in the
    afternoon of days 4, 3 and 2 pre-harvest, daily during harvest, and
    three days thereafter.  Samples were transported cooled in ice and
    assayed within six hours by a modified Ellman method.  Urinary
    diethylphosphates were assayed on early morning urine samples
    collected on days 6, 5, 4 and 1 before harvest, daily during
    harvest, and days 1 and 2 thereafter.  No symptoms or clinical signs
    were recorded that could be attributed to anticholinesterase
    effects.  There was a gradual decline in plasma cholinesterase
    levels during the harvest, which recovered after the end of the
    harvest.  This effect was not seen in controls nor in red blood cell
    cholinesterase level in either test or control groups.  Ethyl
    phosphate metabolites were found in the urine of the test group
    (Baugher, 1989).  A similar study was carried out on French apple
    pickers (Vogel, 1991).  No clinical signs, symptoms suggestive of
    anticholinesterase toxicity, or significant depression of plasma or
    erythrocyte cholinesterase were observed.

         In 1966-1979, eleven pesticide incidents involving the
    agricultural use of phosalone were reported to the USEPA's Pesticide
    Incident Monitoring System (Hodgson & Smith, 1992).  The antidote
    dietixim (a cholinesterase reactivator) was effective in human
    phosalone poisoning (Kundiev & Kagan, 1992). 

    COMMENTS

         After oral administration, phosalone was moderately well
    absorbed, 15-25% appearing in the faeces.  Phosalone was extensively
    metabolized to phosphorothioates, phosphorodithioates and
    3-methylthiomethyl 6-chloro-benzoxazolone, the last of which is
    subsequently metabolized ultimately to 3-methylsulfonylmethyl 6-
    chlorobenzoxazolone.

         Pure phosalone is almost certainly not a cholinesterase
    inhibitor, but acquires inhibitory activity after conversion to
    phosalone oxon  in vivo.

         The acute oral toxicity varies with species, but is in the
    region of 100-200 mg/kg bw in rodents.  Phosalone has been
    classified as moderately hazardous by WHO.

         There were two short-term studies in rats which could be used
    to give NOAELs.  In a five-week oral gavage study in rats at doses
    of 0, 7.5 or 15 mg/kg bw/day, the NOAEL or 7.5 mg/kg bw/day based on
    brain cholinesterase inhibition.  In an eight-week study in rats
    using dietary concentrations of 0, 10, 100, 300, 600 or 1200 ppm,
    the NOAEL was 10 ppm (equal to 0.87 mg/kg bw/day), based on brain
    cholinesterase inhibition.  It is possible that NOAELs could have
    been established at 100 or 300 ppm, but the dose rates for those
    groups were increased to 2400 and 4800 ppm, respectively, after 5
    weeks to establish a maximum tolerated dose.

         Five studies were carried out in dogs.  In a one-month oral
    dosing study in dogs, a NOAEL could not be determined as plasma and
    erythrocyte cholinesterase depression were seen at the lowest dose
    (7.5 mg/kg bw/day).  In another one-month study using dietary
    concentrations of 0, 12.5, 25 or 37.5 ppm, the NOAEL was the highest
    level, which was equal to 0.81 mg/kg bw/day; although plasma
    cholinesterase depression was seen in the study, neither erythrocyte
    nor brain cholinesterase activity was depressed.  In a 6-month study
    in dogs using dietary concentrations of 0, 10 or 25 ppm, although
    plasma and erythrocyte cholinesterase were depressed, the brain
    enzyme was not, so the NOAEL was the highest dose (equivalent to
    0.63 mg/kg bw/day).  In a two-year study in beagle dogs, males and
    females were fed phosalone in the diet at concentrations of 0, 100,
    200 or 1000 ppm.  The NOAEL was 200 ppm, equivalent to 5 mg/kg
    bw/day, based on brain cholinesterase depression, body-weight loss
    and elevated alanine aminotransferase at the highest dose.  In a
    more recent one-year study in dogs using dietary concentrations of
    0, 5, 25 or 300 ppm phosalone, the NOAEL was 25 ppm (equal to 0.89
    mg/kg bw/day), based on brain cholinesterase depression at 300 ppm. 
    The overall NOAEL for dogs was considered to be 200 ppm, in view of
    the spacing of the doses in the most recent study.

         In a lifetime carcinogenicity study in mice, phosalone was
    given at dietary concentrations of 0, 15, 50 or 150 ppm. The NOAEL
    was 150 ppm, equal to 23 mg/kg bw/day, based on the lack of
    depression of brain cholinesterase activity, although plasma and red
    blood cell cholinesterase depression were seen at this level.  There
    was no evidence of carcinogenicity. 

         In a two-year study in rats using concentrations of 0, 25, 50
    or 250 ppm phosalone in the diet, the NOAEL was 50 ppm, equivalent
    to 2.5 mg/kg bw/day, based on brain cholinesterase depression at the
    highest dose. In a second 2-year study in rats, dietary
    concentrations of 0, 5, 50 or 1000 ppm were used, the highest dose
    being reduced to 500 ppm later in the study. There was a
    statistically significant increase in the prevalence of testicular
    atrophy and reduction in testicular weight in both the high and mid-
    dose groups and a dose response across all groups for both effects. 
    The Meeting concluded that the NOAEL was < 5 ppm, equal to 0.2
    mg/kg bw/day.

         In a teratogenicity study in rats at doses of 0, 2, 10 or 20
    mg/kg bw/day, the NOAEL was 10 mg/kg bw/day for both maternal
    toxicity and fetotoxicity.  In a study in rabbits using doses of 0,
    2, 6 or 18 mg/kg bw/day, the NOAEL was the highest dose.  In another
    study in rabbits, using doses of 0, 1, 10 or 20 mg/kg bw/day, the
    NOAEL was 10 mg/kg bw/day based on maternal toxicity.  Phosalone was
    not teratogenic in either the rat or rabbit.

         Two multigeneration reproduction studies in rats were reviewed. 
    In the first study, using dietary concentrations of phosalone of 25
    or 50 ppm, no adverse effects were observed.  The NOAEL was > 50
    ppm, equivalent to 2.5 mg/kg bw/day.  In the second study, in which
    phosalone was administered at dietary concentrations of 0, 10, 50 or
    400 ppm, the NOAEL was 50 ppm (equivalent to 2.5 mg/kg bw/day) based
    on retarded pup growth and plasma and erythrocyte cholinesterase
    depression.

         Phosalone has been adequately tested in a series of  in vitro
    and  in vivo genotoxicity assays.  The Meeting concluded that
    phosalone was not genotoxic.

         There is no evidence that phosalone has potential to cause
    organophosphate-induced delayed neuropathy.

         Pralidoxime salts and obidoxime are both effective in
    experimental phosalone poisoning.

         No human study was available from which a NOAEL could be
    derived.

         An ADI of 0-0.001 mg/kg bw was established based on the lowest
    dose (0.2 mg/kg bw/day) in the recent two-year study in rats.  A
    200-fold safety factor was used because of concerns that the trend
    for the occurrence of testicular atrophy and reduction in testis
    weight existed across all groups.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    150 ppm, equal to 23 mg/kg bw/day (two-year study)

         Rat:      < 5 ppm, equal to 0.2 mg/kg bw/day 
                   (two-year study)
                   50 ppm, equivalent to 2.5 mg/kg bw/day
                   (multigeneration reproduction study)

         Rabbit:   10 mg/kg bw/day (teratology study)

         Dog:      200 ppm, equivalent to 5 mg/kg bw/day 
                   (several studies)

    Estimate of acceptable daily intake for humans

              0-0.001 mg/kg bw

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

         Explanation of the testicular atrophy seen in the recent study
         in rats.

         Observations in humans.

    REFERENCES

    Allen, P.A. (1989) Unpublished study. Additional evaluation of the
    incidence of resorptions in the studies performed by RCC on the
    effects of phosalone technical on embryonic and fetal development in
    the rabbit. Project 083002, 204423, 082991. RCC Research and
    Consulting Company AG, PO Box, CH 4452 Itingen, Switzerland.
    Supplied to WHO by Rhône-Poulenc.

    Allen, P.A., Frei, D., Mladenovic, P. & Terrier C. (1989a)
    Unpublished study. Embryotoxicity study (including teratogenicity)
    with phosalone technical in the rat. Project 082980. RCC Research
    and Consulting Company AG, PO Box, CH 4452 Itingen, Switzerland.
    Supplied to WHO by Rhône-Poulenc.

    Allen, P.A., Mladenovic, P. & Terrier, C. (1989b) Unpublished study.
    Embryotoxicity study (including teratogenicity) with phosalone
    technical in the rabbit. Project 083002. RCC Research and Consulting
    Company AG, PO Box, CH 4452 Itingen, Switzerland. Supplied to WHO by
    Rhône-Poulenc.

    Barker, M.H., Smith, T.G., Buist, D.P., Crook, D., Morrow, J. &
    Gopinath, C. (1992) Unpublished study. Phosalone dietary toxicity
    study in beagle dogs. HRC report No. RNP 336/91907. Huntingdon
    Research Centre Ltd, Wooley, Huntingdon, PE18 6ES, England. Supplied
    to WHO by Rhône-Poulenc.

    Barker, M.H. & Sortwell, R.J. (1993) Unpublished study. Phosalone
    (11974 RP). Potential tumorigenic and toxic effects in prolonged
    dietary administration to rats Volume 1. Huntingdon Research Centre
    Ltd, PO Box 2, Huntingdon, Cambridgeshire PE18 6ES. Supplied to WHO
    by Rhône-Poulenc. England

    Baugher (1989). Unpublished study. Exposure of harvesters to Zolone
    (R) EC brand insecticide applied to grapes in California, 1988.
    Project no 29088. Orius Associates, Frederick, Maryland, USA.
    Supplied to WHO by Rhône-Poulenc.

    Benezet, F. & Cartier, J.R. (1980) Unpublished study. Phosalone (11
    974 RP) mutagenicity study on Salmonella typhimurium. Report
    RP/RD/CNG No. 19 234 E of 19th January 1978. Centre Nicolas Grillet,
    94400 Vitry-sur-Seine, France. Supplied to WHO by Rhône-Poulenc.

    Bryson, A.M., Parker, C.A., Offer, J.M. & Farmer, H. (1991)
    Unpublished study. A study of the effect of phosalone on
    reproductive function of two generations in the rat. Report No. RNP
    326/91277. Huntingdon Research Centre Ltd, PO Box 2, Huntingdon,
    Cambridgeshire, PE18 6ES England. Supplied to WHO by Rhône-Poulenc.

    Cifone, M.A. (1989) Unpublished study. Mutagenicity test on
    phosalone technical in the rat primary hepatocyte unscheduled DNA
    synthesis test. HLA study No. 10754-0-447, Hazleton Laboratories
    America Inc 5518 Nicholson Lane, Suite 400, Kensington Maryland
    20895, USA. Supplied to WHO by Rhône-Poulenc.

    Cordier, A. & Bonneau, D. (1985) Unpublished study. Phosalone (11
    974 RP) CHO/HPRT test. Report. ST/CRV/Tox. No. 22 363-E of 10th May
    1985. Rhône-Poulenc Santé, Centre de Recherches de Vitry, 94403
    Vitry-sur-Seine Cedex, France. Supplied to WHO by Rhône-Poulenc.

    Cordier, A. & Fournier, E. (1985) Unpublished study. Phosalone (11
    974 RP) chromosome aberration test in Chinese hamster ovary cells
    (CHO). Report ST/CRV/Tox. No. 435-E of 28th August 1985. Rhône-
    Poulenc Santé, Centre de Recherches de Vitry, 94403 Vitry-sur-Seine
    Cedex, France. Supplied to WHO by Rhône-Poulenc.

    Craine, E.M. (1974a) Unpublished study. Disposition of phosalone-
    14C in a lactating cow. Research report No. EMC 74:17 of the 29th
    April 1974. Hess and Clark Research Department, Ashland, Ohio, USA.
    Supplied to WHO by Rhône-Poulenc.

    Craine, E.M (1974b) Unpublished study. Disposition of phosalone-14C
    in a lactating cow. Research report No. EMC 74:84 of the 25th
    November 1974. Hess and Clark Research Department, Ashland, Ohio,
    USA. Supplied to WHO by Rhône-Poulenc.

    Craine, E.M. (1974c) Unpublished study. The disposition of
    phosalone-14C applied to the skin of a pig. Research report No. EMC
    74:30 of the 14th May 1974. Hess and Clark Research Department,
    Ashland, Ohio, USA. Supplied to WHO by Rhône-Poulenc.

    Craine, E.M. (1975) Unpublished study. The metabolism of phosalone-
    14C in dairy cows. Research report No. EMC 75:51 of the 2nd July
    1975. Hess and Clark Research Department, Ashland, Ohio, USA.
    Supplied to WHO by Rhône-Poulenc.

    Cunny, H. & Siglin, J.C. (19789) Unpublished study. Delayed contact
    hypersensitivity study in guinea-pigs with phosalone technical.
    Study No. 3147.37. Springborn Life Sciences Inc. Spencerville, Ohio
    45887, USA. Supplied to WHO by Rhône-Poulenc.

    Desmoras, M.J. (1979). Unpublished study. Studies on the metabolism
    of phosalone (11974 R.P.), in the mouse, the rat and the rabbit.
    Note RP/RD/CNG No 20 234 of the 20 August 1979. Supplied to WHO by
    Rhône-Poulenc.

    Desmoras, M.J. & Fournel, J. (1968) Unpublished study. Studies on
    the degradation of phosalone (11974 R.P.), in mammals. Note RP -
    DSPh of the 1st March 1968. Rhône-Poulenc, Laboratoires de
    Recherches, 22 Avenue Montaigne, 75 Paris 8, France. Supplied to WHO
    by Rhône-Poulenc.

    Donoso, J., Woodard, M.W. & Woodard, G. (1967) Unpublished study.
    Phosalone safety evaluation by repeated oral administration to dogs
    for 107 weeks. Report dated 7th September 1967. Woodard Research
    Corporation, Herndon, Virginia 22070 USA. Supplied to WHO by Rhône-
    Poulenc.

    Dubost, P. Fournel, J., Ganter, P., Julou, L., Koenig, F. & Myon, J.
    (1963). Unpublished study. Acute toxicity, local tolerance,
    anticholinesterase activity and chronic toxicity in rats and dogs.
    Note DSPh 9, 203 of the 29th March 1963. Centre Nicolas Grillet,
    94400 Vitry-sur-Seine, France. Supplied to WHO by Rhône-Poulenc.

    Fournel, J., Ganter, P., Julou, L., Populaire, P., Myon, J., Pascal,
    S. & Pasquet, J. (1966) Unpublished study. Phosalone (11 974 RP)
    Sub-acute (6-month) toxicity study in the dog. Note RP-DSPh 11 330 E
    of the 14th June 1966. Société des Usines Chimiques Rhône-Poulenc,
    Direction Scientifiques, Laboratoires de Recherche, Centre Nicolas
    Grillet, 94400 Vitry-sur-Seine, France. Supplied to WHO by Rhône-
    Poulenc.

    Fournel, J., Julou, L. & Pasquet, J. (1968) 12244 R.P. Unpublished
    study. Acute toxicity in mice rats and  in vivo anti-cholinesterase
    activity in rats. Note RP - DSPh 12663 (=12665E) of the 1st March
    1968. Société des Usines Chimiques Rhône-Poulenc, Direction
    Scientifiques, Laboratoires de Recherche, 22 Avenue Montaigne, 75
    Paris 8,France. Supplied to WHO by Rhône-Poulenc.

    Goldenthal, E.I., Jessup, D.C. & Rodwell, D.E. (1978) Unpublished
    study. Dominant lethal study in mice. Study carried out for Rhône-
    Poulenc dated the 18th December 1978. International Research and
    Development Corporation, Mattawan, Michigan, 49071, USA.

    Haworth, L. & Lawlor, T.E. (1989) Unpublished study. Mutagenicity
    test on phosalone technical in the Ames  Salmonella/microsome
    reverse mutation assay. HLA study No. 10754-0-401, Hazleton
    Laboratories America Inc., 5518 Nicholson Lane, Suite 400,
    Kensington Maryland 20895, USA. Supplied to WHO by Rhône-Poulenc.

    Heath, S.A.B., Rivett, K.F. & Woolf, N. (1967) Unpublished study.
    Phosalone test for neurotoxicity. Study No. 230857, May and Baker
    Ltd, Dagenham, Essex, England. Supplied to WHO by Rhône-Poulenc.

    Hayward, A. (1969). Unpublished study. Insecticides: a study of the
    effects of "Cyanox" (S-4084) and "phosalone" on rat erythrocyte
    cholinesterase. Report No. PRG/584 (=274359). May and Baker Ltd,
    Ongar, Essex, England. Supplied to WHO by Rhône-Poulenc.

    Hodgson, H.J. & Smith, A.D. (1992). Commercial and residential
    poisoning with anticholinesterases. In: Ballantyne B and Marrs TC
    (ed) Clinical and experimental toxicology of organophosphates and
    carbamates, pp. 352-363. Butterworth-Heinemann, Oxford, England.

    Hopkins, R., Lewis, C.J. & Lewsley, R. (1991). Unpublished study.
    (14C)-phosalone: a study of the absorption, distribution,
    metabolism and excretion in the rat. Report No. 5759-68/93R.
    Hazleton UK, Harrogate, England. Supplied to WHO by Rhône-Poulenc.

    Jones, E.M., Post, K.F., Scott, W.J., Woodyard, M.W., Woodyard, G. &
    Cronin, M.T.I. (1967a) Unpublished study. Phosalone three generation
    reproduction study in the rat. Report dated September 11th 1967.
    Woodyard Research Corporation and Chipman Chemical Company. Supplied
    to WHO by Rhône-Poulenc.

    Jones, M.E., Woodard, M.W., Imming, R.J., Woodard, G. & Cronin,
    M.T.I. (1967b) Unpublished study. Phosalone followed by a
    determination of potentiation activity with the compound Di-syston.
    Report dated August 10th, 1967. Woodyard Research Corporation and
    Chipman Chemical Company. Supplied to WHO by Rhône-Poulenc.

    Kehoe, D.F. (1990) Unpublished study. 8-week dietary toxicity study
    with phosalone in rats. HLA study No. 6224-149, Hazleton
    Laboratories America Inc 3301 Kinsman Boulevard, Madison, Wisconsin
    53704, USA. Supplied to WHO by Rhône-Poulenc.

    Knaak, J.B., Maddy, K.T., Gallo, M.A., Lillie, D.T., Craine, E.M &
    Serat, W.F. (1978) Worker re-entry study involving phosalone
    application to citrus groves.  Toxicol Appl. Pharmacol., 46 363-
    374.

    Kundiev, Y.I. & Kagan, Y.S. (1992) Anticholinesterses used in the
    USSR: poisoning, treatment and preventative measures. In: Ballantyne
    B and Marrs TC (ed) Clinical and experimental toxicology of
    organophosphates and carbamates.pp 494-501. Butterworth-Heinemann,
    Oxford, England.

    Kynoch, S.R., Lloyd, G.K., Mallard, J.R., Street, A.E., Gibson,
    W.A., Wadsworth, P.F. & Prentice, D.E. (1979) Unpublished study. The
    effect of repeated applications of phosalone 11974 RP to the skin of
    rabbits for 21 days. Report No. RNP 125/79335. Huntingdon Research
    Centre Ltd, PO Box 2, Huntingdon, Cambridgeshire, PE18 6ES, England.
    Supplied to WHO by Rhône-Poulenc. 

    Marrs, T.C. (1991). Toxicology of oximes used in the treatment of
    organophosphate poisoning.  Adverse drug reactions and Toxicology
     Reviews, 10: 61-72.

    Mazuret, A. (1971) Unpublished study. Phosalone,methyl-azinphos and
    parathion acute toxicity in the rat. Report No. RP -DSPh No. 15544-
    E. Rhône-Poulenc Santé, Centre de Recherches de Vitry, 94403 Vitry-
    sur-Seine Cedex, France. Supplied to WHO by Rhône-Poulenc.

    Morris, J.M. (1983) Unpublished study. Acute delayed neurotoxicity
    study in hens with phosalone. GSRI project No. 411-B51-40, Gulf
    South Research Institute, PO Box 1177, New Iberia, Louisiana 70560,
    USA. Supplied to WHO by Rhône-Poulenc.

    Murli, H. (1989) Unpublished study. Mutagenicity test on phosalone
    technical in an in vitro cytogenetic assay measuring chromosomal
    aberration frequencies in Chinese hamster ovary (CHO) cells. HLA
    study No. 10754-0-437, Hazleton Laboratories America Inc., 5518
    Nicholson Lane, Suite 400, Kensington, Maryland 20895, USA. Supplied
    to WHO by Rhône-Poulenc.

    Nelson, L.W., Geil, R.G. & Spicer, E.J. (1980) Unpublished study.
    Phosalone lifetime oncogenicity study in mice. International
    Research and Development Corporation, Mattawan, Michigan 49071, USA.
    Report 347-009, submitted June 23rd, 1980. Supplied to WHO by Rhône-
    Poulenc.

    Noel, P.R., Rivett, K.F., Osborne, B.E. & Street, A.E. (1970)
    Unpublished study. Phosalone dietary intake in beagle dogs for four
    weeks. Report No. 3619/70/431. Huntingdon Research Centre Ltd, PO
    Box 2, Huntingdon, Cambridgeshire, PE18 6ES, England. Supplied to
    WHO by Rhône-Poulenc.

    Owen, P.E. (1985) Unpublished study.6-chlorobenzoxolone: 13 week
    oral (dietary administration) study in the rat with a 28-day
    treatment-free period. Report No. 4229-198/14. Hazleton UK, Otley
    Road, Harrogate, England. Supplied to WHO by Rhône-Poulenc.

    Pasquet, J. (1969) Unpublished study. Study of the teratogenic
    activity of phosalone (11974 RP) on the chick embryo and on the
    rabbit. Note RP - DSPh 13447E of the 7th February 1969 (translation
    no 2707). Centre Nicolas Grillet, 94400 Vitry-sur-Seine, France.
    Supplied to WHO by Rhône-Poulenc.

    Pasquet, J. (1971) Unpublished study. Phosalone (11 974 R.P.)
    toxicité aigüe chez la ratte par voie percutanée. Note RP - DSPh
    15481 of the 28th June 1971. Centre Nicolas Grillet, 94400 Vitry-
    sur-Seine, France. Supplied to WHO by Rhône-Poulenc.

    Pasquet, J. & Fournier, E. (1980) Unpublished study. Phosalone (11
    974 RP) micronucleus test in the mouse. Report.RP/RD/CNG No 557-E of
    8th April 1980. Rhône-Poulenc Santé, Centre de Recherches de Vitry,
    94403 Vitry-sur-Seine Cedex, France. Supplied to WHO by Rhône-
    Poulenc.

    Pasquet, J. & Mazuret, A. (1970) Unpublished study. Obidoxime
    chloride (Toxogonin R Merck = 24,590 R.P. chloride) acute
    intraperitoneal toxicity in the mouse and antidotal effect on the
    acute oral toxicity in the mouse of phosalone (11974 RP) RP - DSPh
    No. 14514-E. Rhône-Poulenc Santé, Centre de Recherches de Vitry,
    94403 Vitry-sur-Seine Cedex, France. Supplied to WHO by Rhône-
    Poulenc.

    Pasquet, J., Mazuret, A., Vaissere, J. & Gaildrat (1983a)
    Unpublished study. Chloromethyl-3 chloro-6 benzoxolone (16891 R.P.)
    - acute toxicity in the rat by the intraperitoneal route. Report
    ST.CRV/Tox No. 21971. Rhône-Poulenc Santé, Centre de Recherches de
    Vitry, 94407 Vitry-sur-Seine Cedex, France. Supplied to WHO by
    Rhône-Poulenc.

    Pasquet, J., Mazuret, A. & Vaissere, J. (1983b) Unpublished study.
    Chlorométhyl-3 chloro-6 benzoxolone (16891 R.P.) - eau de lavage de
    la solution chlorométhyléique - irritation cutanée primaire chez le
    lapin. Note No ST.CRV/Tox. No. 21972. Rhône-Poulenc Santé, Centre de
    Recherches de Vitry, 94407 Vitry-sur-Seine Cedex, France. Supplied
    to WHO by Rhône-Poulenc.

    Pasquet, J. & Mazuret, A. (1973a). Unpublished study. Phosalone
    oxygen analog (12244 R.P.) acute percutaneous toxicity in the rat.
    SUCRP - DSPh No.16979. Rhône-Poulenc,Laboratoires de Recherches, 22
    Avenue Montaigne, 75 Paris 8, France. Supplied to WHO by Rhône-
    Poulenc.

    Pasquet, J. & Mazuret, A. (1973b). Unpublished study. Hydroxymethyl-
    3 chloro-6 benzoxolone (16 236 RP) toxicité et tolérance locale. RP)
    acute percutaneous toxicity in the rat. Note SUCRP - DSPh No.
    17144.Rhône-Poulenc Santé, Centre de Recherches de Vitry, 94403
    Vitry-sur-Seine Cedex, France. Supplied to WHO by Rhône-Poulenc.
    Supplied to WHO by Rhône-Poulenc.

    Pasquet, J. & Mazuret, A. (1977). Unpublished study. Phosalone (11
    974 RP) guinea-pig skin sensitization study. Report RP/RD/CNG No.
    19117 of 27th April 1977. Centre Nicolas Grillet, 94400 Vitry-sur-
    Seine, France. Supplied to WHO by Rhône-Poulenc.

    Pasquet, J. & Mazuret, A. (1980). Unpublished study. Metabolites of
    phosalone (11 974 RP) : compounds 19889 RP, 19889 RP and 19914 RP.
    Acute oral toxicity in the mouse. Report C.R. Vitry/CNG. No. 20 736-
    E of 12th November 1980. Centre Nicolas Grillet, 94400 Vitry-sur-
    Seine, France. Supplied to WHO by Rhône-Poulenc.

    Pasquet, J., Mazuret, A., Fournel, M. & Koenig, M. (1976)
    Unpublished study. Acute oral and percutaneous toxicity of phosalone
    (R.P.11974) in the rat, in comparison with azinphosmethyl and
    parathion. Note RP/RD/CNG No. 18 550 EP/LR of 27th February 1976.
    Centre Nicolas Grillet, 94400 Vitry-sur-Seine, France. Supplied to
    WHO by Rhône-Poulenc.

    Reddy, S.J., Reddy, B.V. & Ramamurthy, R. (1992). Impact of chronic
    phosalone toxicity on Bohr factor and oxygen equilibrium curves of
    rat.  Biochem Inter. 26: 171-179.

    Rhône-Poulenc (1968) Unpublished study. 12244 R.P. oxygen analog of
    phosalone acute oral toxicity and anticholinesterasic activity  in
     vitro. Note RP - DSPh 12664 of the 20th February 1968. Société des
    Usines Chimiques Rhône-Poulenc, Direction Scientifiques,
    Laboratoires de Recherche, 22 Avenue Montaigne, 75 Paris 8, France.
    Supplied to WHO by Rhône-Poulenc.

    Rhône-Poulenc Inc. (1979) Unpublished study. Phosalone dairy cow
    feeding study. ADC project #475A, B of the 6th July 1968. Rhône-
    Poulenc Inc., Agricultural Division, PO Box 125, Black Horse Lane,
    Monmouth Junction, New Jersey 08852, USA. Supplied to WHO by Rhône-
    Poulenc.

    Rhône-Poulenc Inc. (1980a) Unpublished study. Residue determination
    of phosalone and its oxygen analog in the milk and tissues of dairy
    cattle by electron capture gas chromatography. ADC project #475D of
    the 22nd September 1968. Rhône-Poulenc Inc., Agricultural division,
    PO Box 125, Black Horse Lane, Monmouth Junction New Jersey 08852,
    USA. Supplied to WHO by Rhône-Poulenc.

    Rhône-Poulenc Inc. (1980b) Unpublished study. Residue determination
    of metabolites containing the chlorobenzoxazole and
    chloroaminoiphenol moieties in the milk and tissues from dairy
    cattle fed phosalone. ADC project #475D1 of the 22nd September 1968.
    Rhône-Poulenc Inc., Agricultural division, PO Box 125, Black Horse
    Lane, Monmouth Junction, New Jersey 08852, USA. Supplied to WHO by
    Rhône-Poulenc.

    Rhône-Poulenc Inc. (1980c) Unpublished study. Validation of
    analytical methods of phosalone and its metabolites in milk and
    animal tissues. ADC project #496 of the 22nd September 1968. Rhône-
    Poulenc Inc., Agricultural Division, PO Box 125, Black Horse Lane,
    Monmouth Junction, New Jersey 08852, USA. Supplied to WHO by Rhône-
    Poulenc.

    Safonov, N.M. (1968) (Toxicological characteristics of a new
    organophosphorus insecticide: phosalone preliminary results).
    Gigiena truda professional, nye zabolevanija, 12, 43 - Translation
    supplied to WHO by Rhône-Poulenc.

    SERB (1988) Contrathion, pralidoxime, pralidoxima, Data Sheet.
    Laboratoires SERB, 53 Rue de l'Isle-Adam, 75020, Paris, France.

    Siglin, J.C., Jenkins, P.K., Rush, R.E., Liao, J.T. & Rodwell, D.E.
    (1979) Unpublished study. Primary eye irritation study of phosalone
    technical in rabbits with washout (EPA). Study No. 3147.36.
    Springborn Life Sciences, Inc., Spencerville, Ohio 45887, USA.
    Supplied to WHO by Rhône-Poulenc.

    Vanrel, B., Thenaisie, S., Gascoin, M.N., Vanrell, B., Glomot, R. &
    Le Bigot, J.F. (1989) Unpublished study. Metabolite of phosalone in
    soil reverse mutation assay  in vitro Ames test. Study No. 5137
    MMO. Rhône-Poulenc Agrochimie, Lyon, France. Supplied to WHO by
    Rhône-Poulenc.

    Vogel, W.(1991). Unpublished study. Exposure of harvesters to
    residues of Zolone(R) flo (Phosalone) insecticide applied to apples
    in France in 1989. RCC project No 241683. RCC Umweltchemie AG, PO
    Itingen CH 4452 Switzerland. Supplied to WHO by Rhône-Poulenc.

    Woodard, M.W., Cockrell, K.O., Woodyard, G. & Cronin, M.T.I. (1966)
    Unpublished study. Phosalone demyelination study in chickens. Report
    submitted April 7th, 1966 to the Chipman Chemical Company. Woodard
    Research Corporation. Supplied to WHO by Rhône-Poulenc.

    Woodard Research Corporation (1967) Unpublished study. Phosalone
    safety evaluation by repeated oral administration to rats for 103-
    104 weeks. Report submitted April 7th, 1966 to the Chipman Chemical
    Company. Supplied to WHO by Rhône-Poulenc.

    Weill, N. (1988) Unpublished study. Ames test on  Salmonella
     typhimurium on 50221 RP. Report No. 803380. Hazleton France.
    Supplied to WHO by Rhône-Poulenc.

    WHO (1986) Environmental Health Criteria 63. Organophosphorus
    insecticides: a general introduction. World Health Organization,
    Geneva, p 63.

    WHO (1992). The WHO recommended classification of pesticides by
    hazard and guidelines to classification 1992-1993 (WHO/PCS/92.14).
    Available from the International Programme on Chemical Safety, World
    Health Organization, Geneva, Switzerland.


    See Also:
       Toxicological Abbreviations
       Phosalone (ICSC)
       Phosalone (WHO Pesticide Residues Series 2)
       Phosalone (WHO Pesticide Residues Series 5)
       Phosalone (Pesticide residues in food: 1976 evaluations)
       Phosalone (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)
       Phosalone (JMPR Evaluations 2001 Part II Toxicological)