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    DIAZINON

    First draft prepared by
    E. Bosshard
    Federal Office of Public Health,
    Schwerzenbach, Switzerland

    EXPLANATION

         Diazinon was previously evaluated by the Joint Meeting in 1963,
    1965, 1966 and 1970 (Annex I, references 2, 3, 6, 14).  An ADI of 0-
    0.002 mg/kg bw was allocated in 1966, based on a NOAEL of 0.02 mg/kg
    bw/day in human volunteers (Annex I, reference 7).  The compound was
    reviewed at the present Meeting on the basis of the CCPR periodic
    review programme.  This monograph summarizes the data received since
    the previous evaluation and contains relevant data from the previous
    monographs and monograph addenda.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

         The fate of diazinon in various animal species was studied
    after oral and topical applications using unlabelled and
    radiolabelled diazinon in chicken, rats, guinea-pigs, dogs, sheep,
    goats and cows.  Additional studies were performed  in vitro using
    tissue slices or cell fractions from different tissues and various
    species to investigate the biotransformation of the compound.  A
    short summary on the metabolism of diazinon has been published
    (Miyamoto 1976).

    Absorption, distribution and excretion

    Oral studies

    Rats

         After the application of a single oral dose of 0.8 mg/rat (4
    mg/kg bw) 14C-labelled diazinon (labels at 2-14C, 4-14C or ethoxy-
    14C) to four male and two female Wistar rats, radioactivity was
    eliminated practically completely during the 168-hours observation
    period with either label.  Excretion of applied radioactivity
    amounted to 65-80% in urine, and 16-24% in faeces.  The excretion
    half-time was estimated to be 12 hours for the pyrimidine-labelled
    and 7 hours for the ethoxy-labelled compound.  After the application
    of side-chain labelled material, about 6% of the applied dose was
    eliminated as 14CO2.  The absence of radioactive CO2 in the
    expired air after application of ring-labelled diazinon shows that
    no cleavage of the pyrimidine ring occurred (Mücke  et al., 1970).

         After feeding male rats during 10 days 0.1 mg/rat/day (0.5
    mg/kg bw/day) of 2-14C-diazinon, 2.9% of the applied dose was found
    in the essential organs 6 hours after the final application, whereas
    2 days after cessation of treatment the radioactivity was below the
    detection limit (< 0.1%).  These results indicate that no
    accumulation of diazinon or its metabolites occurs in the body
    (Mücke  et al., 1970; Annex I, reference 15).

         In a more recent study, two groups of rats (5/sex/dose) were
    treated with a single oral dose of 10 or 100 mg/kg bw 14C-diazinon. 
    A third group was treated daily with unlabelled diazinon at a dose
    level of 10 mg/kg bw during 14 days, followed by the same dose of
    14C-labelled diazinon on day 15.  The elimination of the
    radioactivity was monitored over a seven-day period.  14C-
    elimination of radioactivity was rapid and occurred mainly via the
    urinary tract.  In the low-dose group, 93% of the applied

    radioactivity was excreted in the urine in males and 86% in females
    within 24 hours.  At the high-dose level, an average of 91% and 58%
    in males and females, respectively, was excreted in the first 24
    hours.  After preconditioning, about 90% of the 14C-dose was
    excreted within 24 hours in both sexes.  The total amounts
    eliminated over the 7-day observation period did not differ between
    the various dosing regimens.  Total urinary excretion amounted to
    96%, and faecal elimination to 3%.  These results suggest that
    complete absorption occurs following intragastric administration and
    supports the hypothesis that the small amount of faecal
    radioactivity found may be of biliary origin.  Tissue concentrations
    of 14C-diazinon and metabolites seven days after dosing were mostly
    less than 0.05 ppm for low-dose and pre-conditioned animals.  In
    high-dose animals, residue levels in different organs varied between
    0.1 and 0.4 ppm (red blood cells) with female rats showing
    consistently slightly higher tissue residues than males.  The 14C
    in the blood was associated primarily with the cellular fraction,
    suggesting that binding occurred (Capps  et al., 1989; Craine
    1989).

    Guinea-pigs

         32P-Labelled diazinon was administered orally or
    subcutaneously to male guinea-pigs at a dose level of 45 mg/kg bw. 
    After oral dosing, 80% of the applied radioactivity was excreted in
    the urine within 48 hours, whereas faecal excretion was 10% mostly
    eliminated within the first day.  After subcutaneous dosing, urinary
    excretion was 53%, faecal excretion was minimal.  Highest residues
    were found in the caecum corresponding to 36% and 5% of the
    radioactivity administered 16 hours after oral and subcutaneous
    dosing, respectively.  About 1-2% of the radioactivity was found in
    the liver after 16 hours.  During the 7-day observation period, over
    87% of the dose was eliminated in the excreta, mainly in the urine,
    indicating that the large amounts found in the caecum after oral
    treatment ultimately left the body via the kidneys.  The
    accumulation of radioactivity in the caecum also following
    subcutaneous injection indicates that this tissue may play a role in
    metabolism or elimination of diazinon and/or its metabolites in
    guinea-pigs (Kaplanis  et al., 1962).

    Hens

         After oral administration of 14C-diazinon to 4 laying hens by
    capsule for 7 consecutive days at daily doses of 2.8 mg/animal
    corresponding to 25 ppm, 79% of the total dose applied was
    eliminated in the excreta and 0.1% was found in the tissues at
    sacrifice, about 24 hours after the final dose.  Highest tissue
    levels of 0.15 ppm were found in the kidney.  Maximum residues in
    eggs amounted to 0.07 ppm.  The treatment caused some reduction in

    body weight in most animals but had no influence on the general
    health condition (Simoneaux, 1988b; Simoneaux  et al., 1988;
    Burgener & Seim 1988).

    Dogs

         In an intravenous study, 14C-ethoxy-labelled diazinon was
    injected at a dose level of 0.2 mg/kg bw.  After 24 hours, 58% of
    the applied radioactivity was recovered in urine (Iverson  et al.,
    1975).

    Goats

         Two lactating goats were treated daily with 14C-diazinon by
    capsule for four consecutive days at a dose of 150 mg/animal (4
    mg/kg bw).  Urinary excretion amounted to 64% of the applied dose,
    whereas faeces contained an average of 10%.  Highest residues of 2
    ppm 14C were found in kidneys whereas the levels in the other
    tissues ranged from 0.2 to 1.2 ppm.  Highest levels in milk were
    0.5 ppm (Pickles & Seim 1988; Simoneaux, 1988a,c; Simoneaux  et al.,
    1988).

    Cows

         A lactating cow was orally treated by capsule with a dose level
    of 20 mg/kg bw of 32P-labelled diazinon.  About 74% of the applied
    dose was excreted in the urine within 36 hours and 6% in the faeces. 
    The cumulative percentage of total dose in milk 36 hours after
    treatment was less than 0.08% (Robbins  et al., 1957).

         In summary, diazinon is rapidly and almost completely absorbed
    and eliminated after oral application.  Excretion occurs mainly via
    the kidney.  Diazinon or its metabolites do not accumulate in the
    body.

    Dermal studies

    Rats

         Groups of 4 rats were dermally treated with dose levels of 1 or
    10 mg/kg bw 14C-diazinon dissolved in tetrahydrofuran.  Renal
    excretion ranged from 70-80% of the applied dose at both dose levels
    over the 6 days observation period; elimination in faeces was
    usually less than 10%.  Most of the radioactivity was eliminated
    within 48 hours after application.  After 72 hours, less than 1% of
    the applied dose was found on the skin.  Highest tissue residues
    were measured 8 hours after treatment varying between 0.1 and 0.4
    ppm in the low-dose animals.  Residues in the high-dose animals were
    correspondingly higher.  These results show that diazinon is easily
    absorbed through the skin (Ballantine  et al., 1984).

    Sheep

         Two sheep were dermally exposed for 3 days to diazinon at a
    daily dose of 40 mg/kg bw.  The sheep were sacrificed six hours
    after the final application.  Radiolabelled residues were observed
    in all tissues at levels ranging from 2.2 to the highest value of 13
    ppm in kidney.  Because the study was designed to allow the
    identification of metabolites in sheep tissue after topical
    application of 14C-diazinon, no results were presented with respect
    to elimination of the compound (Capps  et al., 1990; Pickles & Seim
    1990).

    Biotransformation

    In vitro studies

         Diazinon was incubated with liver microsomes from different
    avian species, rat, guinea-pig, pig, sheep and cow.  Metabolites
    identified included hydroxydiazinon, isohydroxydiazinon,
    dehydroxydiazinon, their oxons and diazoxon.  Yields and rates of
    production of these metabolites varied between the different species
    (Machin  et al., 1975).

          In vitro studies using microsomal preparations from rat liver
    showed that diazinon was converted rapidly to water-soluble
    metabolites (Dahm, 1970).  The oxidation of diazinon by the
    microsomal enzyme system fortified with NADPH or NADH occurred
    through hydroxylation of the ring alkyl side chain, desulfuration,
    and cleavage of the arylphosphate bound.  The major metabolic
    products of diazinon were hydroxydiazinon, diazoxon and
    hydroxydiazoxon.  Other metabolites identified were 2-isopropyl-4-
    methyl-6-hydroxypyrimidine, 2-(2'-hydroxy-2'-propyl)-4-methyl-6-
    hydroxypyrimidine, diethyl-phosphorothioic acid and
    diethylphosphoric acid, which were all produced by the cleavage of
    the arylphosphate bound (Shishido  et al., 1972a).  Diazoxon, the
    active toxicant, formed by the oxidation of diazinon through
    desulfuration was degraded mainly by hydrolysis resulting in the two
    metabolites diethylphosphoric acid and 2-isopropyl-4-methyl-6-
    hydroxypyrimidine (Shishido & Fukami 1972).  A glutathione conjugate
    S-(2-isopropyl-4-methyl-6-pyrimidinyl) glutathione was also
    identified.  This compound was formed by conjugation of reduced
    glutathione and the pyrimidinyl moiety of diazinon with the
    simultaneous cleavage of the phosphate ester bound (Shishido  et
     al., 1972b).  In insects, diazoxon is degraded slowly by the
    microsomal mixed function oxidase system, while no diazoxon-
    hydrolyzing enzyme was found (Shishido & Fukami 1972; Yang  et al.,
    1971).

    In vivo studies

         Biotransformation of diazinon has been extensively studied in
    numerous mammalian species and also in hens.  Considerable breakdown
    occurs in all species studied.

    Rats

         Metabolic studies in rats treated with 14C-labelled diazinon
    (2-14C, 4-14C or ethoxy-14C labels) by the oral route (4 mg/kg bw)
    showed that the parent compound is degraded rapidly yielding the 3
    pyrimidinols, 2-isopropyl-6-methyl-4(1H)-pyrimidinone, 2-(alpha-
    hydroxyisopropyl)-6-methyl-4(1H)-pyrimidinone and its beta isomer as
    main urinary metabolites.  A number of polar unidentified substances
    was also found.  In addition to small amounts of unchanged diazinon
    the same metabolites were also found in faeces.  Diazoxon as a
    labile and transient intermediate was absent in the extracts of
    urine and faeces.  The absence of radiolabelled CO2 indicated that
    no cleavage of the pyrimidine ring took place.  The intravenous
    application of these main metabolites revealed that the pyrimidinols
    are further degraded yielding some unidentified polar metabolites
    (Mücke  et al., 1970).

         In a more recent study, rats were treated with single oral
    doses of 10 or 100 mg/kg bw of 14C-labelled diazinon.  Another
    group was preconditioned for 14 days with unlabelled diazinon and
    then dosed with 10 mg/kg bw of 14C-labelled diazinon.  A similar
    metabolic pattern as in the above-mentioned study was found.  In
    urine, the 3 pyrimidinols accounted for 65% of the applied
    radioactivity, whereas 15% consisted of polar non-identified
    metabolites and trace amounts of diazinon (0.11%), hydroxydiazinon
    (0.12%) and diazoxon (0.14%) (Capps  et al., 1989).

    Dogs

         Metabolic studies in dogs were performed after oral and
    intravenous administration of ring-labelled and ethoxy-labelled
    diazinon, respectively.  After i.v. application the 14C-ethoxy-
    labelled diazinon, diethyl phosphoric acid (DEP) and diethyl
    phosphorothioic acid (DETP) were detected in urine, whereas after
    the oral dosing with the 14C-ring-labelled diazinon, the
    pyrimidinols 2-isopropyl-6-methyl-4(1H)-pyrimidinone and 2-(alpha-
    hydroxyisopropyl)-6-methyl-4(1H)-pyrimidinone could be identified. 
    In contrast to the results of an  in vitro study (Shishido & Fukami
    1972) no evidence  was given from this dog study that the cleavage
    of the ester bond was glutathione-mediated (Iverson  et al., 1975).

    Cows

         In a metabolic study with cows treated with an oral dose of 20
    mg/kg bw 32P-labelled diazinon, DEP and DETP were found as urinary
    end products of diazinon metabolism (Robbins  et al., 1957).

         The pyrimidinols were also identified as the major metabolites
    in urine and tissues of dermally treated sheep (Capps  et al., 
    1990) and orally treated goats and hens (Simoneaux 1988c,d;
    Simoneaux  et al., 1988).  The respective glucuronides were also
    identified in these species (Sachsse & Bathe, 1976; Simoneaux
    1988c,d; Simoneaux  et al., 1989; Capps  et al., 1990).

         In summary, diazinon was found to be readily degraded and the
    metabolites formed were mainly eliminated via the kidneys.  The main
    degradative pathway of diazinon in mammals includes the
    oxidase/hydrolase-mediated cleavage of the ester bond leading
    directly and via diazoxon to the pyrimidinol derivative 2-isopropyl-
    6-methyl-4(1H)-pyrimidinone, which is further oxidized at the
    isopropyl substituent resulting in the hydroxy pyrimidinols either
    excreted as such or further degraded to more polar metabolites. 
    Metabolites with an intact pyrimidinyl phosphorus ester bond such as
    hydroxydiazinon, diazoxon and its hydroxy derivative are only
    transient products which are ultimately cleaved to their
    corresponding pyrimidine analogs.  The uncleaved products were found
    only in  in vitro studies (Hagenbuch & Mücke 1985).

         Figure 1 presents the proposed metabolic pathway of diazinon in
    mammals.

    Toxicological studies

    Acute toxicity studies

         The results of the acute studies are summarized in Table 1.

         Clinical signs of acute toxicity are consistent with those
    caused by organophosphates including decrease of spontaneous
    activity, sedation, dyspnea, ataxia, tremors, convulsions,
    lacrimation and diarrhoea.  The symptoms were reversible in
    surviving animals.

         The studies on the acute toxicity of diazinon were conducted
    with technical grade material of 95.7-97.1% purity.  Samples tested
    before 1979 show a much higher acute toxicity particularly due to
    the content of the highly toxic by-product tetraethyl-pyrrophosphate
    (TEPP).  Improvements in the manufacturing of diazinon did reduce
    the content of toxic by-products (Annex I, reference 15, Ciba-Geigy
    1992).  WHO has classified diazinon as moderately hazardous (WHO,
    1992).

        Table 1.  Acute toxicity of diazinon (technical material)
                                                                                            
    Species     Sex     Route       LD50/LC50*          Purity       Reference
                                 (mg/kg bw)/(mg/l)         %
                                                                                            

    Mouse       M,F     oral            187                ?         Bathe, 1972a

    Rat         M,F     oral            422              97.1        Bathe & Gfeller, 1980
                M,F     oral           1250                ?         Kuhn, 1989a
                M,F     oral            300              95.7        Piccirillo, 1978
                M,F     oral           1012              96.1        Schoch & Gfeller, 1985

    Rat         M,F     dermal       > 2150                ?         Bathe, 1972b

    Rat         M,F     inhalation     2.3*                ?         Holbert, 1989

    Rabbit      M,F     dermal       > 2020                ?         Kuhn, 1989d

                                                                                            
    
    Irritation, sensitization

         Diazinon (tech.) was evaluated for irritation potential in
    rabbit eyes (Kuhn, 1989b) and skin (Kuhn, 1989c).  The compound was
    not considered as an irritant.

         In a skin sensitization study in guinea-pigs, diazinon did not
    reveal a sensitizing potential (Kuhn, 1989e).

    Potentiation studies

         Potentiation studies were conducted with chlordimeform,
    jodfenphos, methacrifos and profenofos.  No potentiation was
    observed after combined application of equitoxic doses (Sachsse &
    Bathe, 1975, 1976, 1977, 1978).

         A marked decrease of the acute toxicity during the degradation
    of diazinon was demonstrated by the studies on the pyrimidinol
    metabolites 2-isopropyl-6-methyl-4(1H)-pyrimidinone and 2-(alpha-
    hydroxyisopropyl)-6-methyl-4(1H)-pyrimidinone (Mücke  et al., 1970;
    Annex I, reference 15).

    FIGURE 01

    Short-term toxicity studies

         Although reported in the summaries of the following studies,
    the inhibition of plasma cholinesterase was not utilized as a
    criterion for the NOAEL, whereas inhibition of the erythrocyte
    cholinesterase activity may be taken as an indicator of an adverse
    effect of anticholinesterase pesticides.  An inhibition of > 20%
    compared to the control activity is regarded as significant (Dressel
     et al., 1980; WHO, 1990).

    Rats

         Two short-term inhalation studies were conducted in rats.  In a
    first study groups of rats (9/sex/group) were exposed to an aerosol
    of diazinon (purity 97.1%; droplet size < 1 µm 30-40%, 1-7 µm 50%)
    for 6 hours a day, 5 days per week for three weeks.  Only the
    animals' snouts were exposed to the aerosol.  The mean
    concentrations were 0, 151, 245 or 559 mg/m3.  The treatment did
    not cause changes in the mortality rate, in haematology,
    macroscopical and histopathological findings or organ weights that
    were attributable to the inhalation of diazinon.  Exophthalmus and
    diarrhoea were observed in animals at all dose levels and tonic-
    clonic muscle spasms occurred in the high-dose animals.  The
    symptoms were reversible.  Food intake at the highest dose level was
    reduced at the beginning of the treatment period.  Body-weight gain
    was reduced in male rats at 245 and 559 mg/m3, and in female rats
    at 559 mg/m3.  Plasma cholinesterase was inhibited at the
    intermediate and high levels, resulting in values corresponding to
    56% and 37% of the activity in control animals, respectively. 
    Erythrocyte cholinesterase was inhibited only at the highest dose
    level (34% of the control activity).  Brain cholinesterase activity
    was dose-dependently reduced at all dose levels resulting in
    activities of 81, 56 and 37% of the control activity in both sexes
    at the low-, medium- and high-dose levels, respectively.  The
    cholinesterase values returned to normal at the end of the 25-day
    recovery period.  The NOAEL in this study was < 151 mg/m3
    (corresponding to an estimated dose of 55 mg/kg bw/day), based on
    lack of significant brain cholinesterase inhibition at the lowest
    dose level (Zak  et al., 1973).

         In a more recent 21-day inhalation study, diazinon (purity 88%;
    particle diameter 0.7-1.4 µm) was administered in a nose-only
    exposure system in rats (10/sex/group).  The intended aerosol
    concentrations were 0, 0.1, 0.3, 1 or 10 mg/m3 (actual: 0, 0.05,
    0.46, 1.57, 11.6 mg/m3).  The animals were exposed during 6 hours a
    day, 5 days per week for 3 weeks.  The treatment did not adversely
    affect body-weight gain, food consumption, haematological
    parameters, organ weights, macroscopy and histopathological
    findings.  At 1 and 10 mg/m3, plasma cholinesterase activity was
    reduced in females by 70% and 50% compared to control animals,

    respectively.  Erythrocyte cholinesterase was inhibited to 60% of
    the control activity at 10 mg/m3 in both sexes, whereas the
    activity of the brain cholinesterase was reduced in females only to
    80% of the control activity at 1 mg/m3, and to 60% in the high-dose
    animals.  The increase of the relative lung weight observed in
    females at 0.3 and 1 mg/m3 but not at the high dose was not
    considered biologically significant.  The NOAEL in this study was
    0.46 mg/m3 (corresponding to an estimated dose of 0.2 mg/kg
    bw/day), based on inhibition of brain cholinesterase at higher dose
    levels (Hartmann, 1990).

         Four groups of rats (Sprague-Dawley; Crl: VAF/Plus CD(SD)Br.;
    15/sex/group) were orally treated with diazinon (purity 87.7%) at
    dietary concentrations of 0, 0.5, 5, 250 or 2500 ppm for 90 days. 
    The treatment had no effect on mortality, water consumption,
    ophthalmoscopy or urinalysis.  Treatment-related occurrence of soft
    faeces, hypersensitivity to touch and sound and in some male animals
    aggressiveness were observed at the 2500 ppm dose level. Moreover,
    hyperactivity was observed in several animals of the high-dose group
    at the end of the study.  Body-weight gain was reduced at 2500 ppm
    by 6% in males and 13% in females compared to control animals.  Food
    consumption was reduced at 2500 ppm sporadically on single days in
    both sexes.  Haematological and biochemical investigations were
    performed in the last study week.  In the highest dose females,
    slight reductions in haemoglobin and haematocrit values, as well as
    an increase of the white blood cell count and reticulocyte count
    were observed.  A dose-dependent decrease in the mean serum
    cholinesterase activity was observed in females and males at 5 ppm
    (22% and 74%, respectively, of activity in control group), at 250
    ppm (3% and 12% of the control activity, respectively) and at 2500
    ppm (2% and 4% of the control activity, respectively).  Erythrocyte
    cholinesterase activity was reduced to 73% and 59% of control
    activity at 250 and 2500 ppm in males and females, respectively.  A
    reduction in brain cholinesterase activity was found at 250 ppm in
    females only (59%) and at 2500 ppm in both sexes resulting in
    activities of 40%-50% of the control activity.  An increase in
    female liver and kidney weights was observed at 2500 ppm. 
    Microscopic evidence of centrolobular hepatocellular hypertrophy was
    observed in single females at 250 ppm and in most females at 2500
    ppm.  The NOAEL in this study was 5 ppm, equal to 0.4 mg/kg bw/day,
    based on erythrocyte and brain cholinesterase inhibition at 250 ppm
    and higher (Singh  et al., 1988).

    Rabbits

         In a dermal toxicity study, groups of albino rabbits
    (5/sex/group) received dermal applications of 0, 1, 5 or 100 mg/kg
    bw diazinon (purity 97.1%; 50% aqueous suspension in PEG 300), 5
    days a week during a 3-week period.  Because of high mortality in
    males at 100 mg/kg bw (4/5 animals died between study days 3 and 6),

    this dose level was reduced to 50 mg/kg bw on day 8 of the study. 
    In high-dose animals, signs of toxicity included anorexia, ataxia,
    tremors, diarrhoea, hypoactivity, hypotonia and salivation.  Body-
    weight gain and food consumption tended to be higher in treated
    animals compared to control animals.  Serum cholinesterase was
    inhibited in both sexes at 100/50 mg/kg bw resulting in values of
    about 37% of the control group activity.  At 5 mg/kg bw, activities
    were 77% and  65% of the  control activity in  males and females,
    respectively.  At 1 mg/kg bw, inhibition was only found in females
    resulting in an activity of 68%.  Erythrocyte acetylcholinesterase
    was inhibited only at 100/50 mg/kg bw resulting in 61% and 68% of
    the control activity in males and females, respectively.  Brain
    acetylcholinesterase was also inhibited only at the highest dose
    level of 100/50 mg/kg bw resulting in values corresponding to 72%
    and 57% of the control activity in males and females, respectively. 
    The only change in organ weights was a decrease in kidney weight in
    females at 100/50 mg/kg bw.  No treatment-related macroscopic or
    microscopic alterations were observed with the exception of slight
    erythema at the application sites.  Histologically a slight
    hyperkeratosis was observed in treated skin of high-dose animals 
    The results of this study indicate a marked percutaneous absorption
    and are thus in agreement with the results of other studies.  The
    NOAEL in this study was 5 mg/kg bw dermal, based on erythrocyte and
    brain cholinesterase inhibition at 100/50 mg/kg bw (Ballantine  et
     al., 1984; Tai & Katz 1984).

    Dogs

         In a 90-day feeding study, diazinon (purity 87.7%) was
    administered to groups of beagle dogs (4/sex/group) at dietary
    concentrations of 0, 0.1, 0.5, 150 or 300 ppm (adjusted for purity). 
    No treatment-related mortalities occurred.  The treatment did not
    adversely affect food consumption, ophthalmoscopy, haematology,
    urinalysis, organ weights or macroscopic findings.  Clinical signs
    such as emesis or bloody faeces were sporadically observed in males
    at 300 ppm and in females at 150 ppm.  Reduced body-weight gain was
    observed in females at 150 ppm and at 300 ppm in both sexes.  In
    males, inhibition of serum cholinesterase was observed resulting in
    activities of 70%, 20% and 15% of that measured in control animals
    at the end of the study at 0.5, 150 and 300 ppm, respectively. 
    Erythrocytes activities corresponding to 75% and 69% of control
    activity were measured at 150 and 300 ppm, whereas in brain the
    acetyl cholinesterase inhibition resulted in 69% and 58% of control
    activity at 150 and 300 ppm, respectively.  In females a reduction
    in acetylcholinesterase activity was observed at 150 and 300 ppm. 
    The inhibition of serum and erythrocyte cholinesterase resulted in
    an activity of about 18% and 70% of control activity, respectively,
    at both dose levels, and brain cholinesterase inhibition resulted in
    70% and 55% of control activity at 150 and 300 ppm, respectively. 
    Other changes of biochemical parameters consisted of a decrease in

    total protein at 300 ppm in males.  The only microscopic alteration
    that might be compound-related was atrophy of the pancreatic acini
    in one male dog of the highest dose group.  The NOAEL in this study
    was 0.5 ppm, equal to 0.02 mg/kg bw/day, based on erythrocyte and
    brain cholinesterase inhibition at 150 ppm and above (Barnes  et
     al., 1988).

         Diazinon has been reported to produce pancreatic acinar lesions
    in dogs at 75 mg/kg bw/day (Frick  et al., 1987).

         In a 52-week oral toxicity study, groups of beagle dogs
    (4/sex/group) were fed diazinon (purity 87.7%) at dietary
    concentrations of 0, 0.1, 0.5, 150 or 300 ppm (adjusted for purity). 
    Due to lack of body-weight gain the dietary concentration of 300 ppm
    was reduced to 225 ppm after 14 weeks of treatment (dose 300/225
    ppm).  Mortality was not increased by treatment and haematology,
    urinalysis, gross pathology and histopathology revealed no changes
    attributable to treatment.  Overt clinical signs of dehydration and
    emaciation became evident in one male at 300/225 ppm.  The symptoms
    remained even though the initial dose was reduced.  Reductions in
    body-weight gain were observed at 150 ppm and higher in males and at
    300/225 ppm in females.  However, no clear-cut dose-response
    relationship was evident and the differences attained statistical
    significance compared to the control group at only some observation
    times.  Food consumption was reduced at 150 ppm and higher, again
    without a clear dose-response relationship, most probably due to
    reduced palatability of the feed admixtures.  Treatment-related
    decreases in acetylcholinesterase activity at dose levels of 0.5 ppm
    and higher were found: serum cholinesterase was reduced at 0.5 ppm
    and higher in males and at 150 ppm and higher in females, resulting
    in activities of about 20% of the activity in the control group at
    150 and 300/225 ppm in both sexes.  Erythrocyte cholinesterase
    activity was also reduced at 150 and 300/225 ppm, where activities
    corresponding to about 70% of the control activity were measured in
    both sexes.  Brain cholinesterase was inhibited at 150 ppm to 75% of
    control activity in females and at 300/225 ppm to 65% and 75% of
    control activity in females and males, respectively.  The NOAEL in
    this study was 0.5 ppm, equal to 0.02 mg/kg bw/day, based on
    erythrocyte and brain cholinesterase inhibition at 150 ppm and above
    (Rudzki  et al., 1991).

    Long-term toxicity/carcinogenicity studies

    Mice

         Groups of mice (B6C3F1 Hybrid; 50 (control 25)/sex/group)
    were administered diazinon (purity 98%) at 0, 100 or 200 ppm over
    103 weeks.  Survival, body weight, clinical signs and pathology were
    investigated.  The treatment had no effect on survival or body-
    weight development.  An increased incidence of hepatocellular

    carcinomas was observed in the low-dose males only.  The incidences
    of hepatocellular carcinomas were 19, 43 and 21% in the control, low
    and high-dose males, respectively, whereas the incidence of liver
    adenomas was not increased in treated animals compared to control
    animals.  The mean incidences of hepatocellular carcinomas in
    historical controls of this mouse strain (18 studies) were reported
    to be 14% (max. 27%) for males and 3% (max. 10%) for females. 
    Concerning the total incidence of carcinomas and adenomas,
    incidences of 29% (max. 58%) and 11% (max. 34%) in males and females
    were reported (personal communication from Ciba Geigy to WHO, 1993). 
    Thus the incidence of hepatocellular carcinomas found in males of
    the low-dose group markedly exceeded the range of historical control
    incidences.  Because no dose-response relationship was evident, the
    result was most probably fortuitous and could not be interpreted as
    providing evidence for a carcinogenic potential of diazinon in mice
    (NCI, 1976).

    Rats

         Groups of rats (Fischer F344; 50 (control 25)/sex/group) were
    fed diazinon (purity 98%) at dietary concentrations of 0, 400 or 800
    ppm for 103 weeks.  Survival, body weight, clinical signs and
    pathology were the parameters investigated.  There was no dose-
    related reduction of survival and the body-weight development was
    similar in control and treatment groups.  Clinical signs of
    hyperactivity were observed in treated males in both dose groups and
    in high-dose females.  The incidence of leukaemia was increased in
    low-dose males (50%) compared to the incidence in the concurrent
    control (20%) and high-dose males (24%).  The leukaemias were of the
    type usually seen in aging F344 rats.  In females, the incidences of
    leukaemia were also higher (12% at 400 ppm and 10% at 800 ppm)
    compared to the concurrent controls (4%).  Historical control
    incidences of leukaemia were reported to be 48% for males (range 32-
    62%) and 27% for females (range 14-15%).  Because of the lack of a
    dose-response relationship, the increase in tumour incidence was
    considered of questionable significance and the results therefore
    could not be interpreted as providing evidence for a tumorigenic
    potential of diazinon in rats (NCI, 1976; NIEHS, 1991).

         Diazinon (purity 87.7%) was administered as feed admixture to
    groups of rats (Sprague-Dawley; 30-40/sex/dose) at concentrations of
    0, 0.1, 1.5, 125 or 250 ppm (adjusted for purity) for up to 98-99
    weeks.  An additional vehicle control group was included in this
    study.  The animals of this dose group were treated with epoxidized
    soybean oil.  Up to 10 rats/sex/group were used for the interim
    sacrifice after at least 52 weeks of treatment.  Another number of
    up to 10 rats/sex from the control and high-dose group were placed
    on a four-week recovery period and sacrificed thereafter.  The study
    was terminated after 98-99 weeks because of decreased survivability
    in the 0.1 ppm male group only, which was unrelated to treatment and

    associated with age-related changes (e.g., senile nephropathy and/or
    pituitary adenoma, both considered to be the result of senescence in
    this rat strain).  This earlier termination was not considered to
    have affected the quality or integrity of the study because a
    sufficient number of animals were at risk in the other treatment
    groups for the development of tumours.  The treatment did not cause
    increased mortality, and did not affect ophthalmological or
    haematological findings, urinalysis or organ weights.  Body-weight
    gain was increased in males at dose levels of 0.1 ppm and higher and
    in some instances in females at 125 ppm and higher compared to the
    untreated control animals.  Because the body-weight gain in the
    vehicle control group also showed an increase compared to the
    untreated controls, the increases in body-weight may reflect an
    increased palatability of the feed admixtures containing the
    epoxidized soybean oil.  In fact the increases in mean body-weight
    gain generally coincided with increases in mean food consumption in
    these dose groups.  Decreases in serum cholinesterase activities
    were observed at concentrations of 1.5 ppm and higher in both sexes,
    resulting in values of about 50% of the control activity at the end
    of the study.  A dose-dependent reduction of erythrocyte
    cholinesterase activity was observed at 125 and 250 ppm resulting in
    activities of 80% and 75% of the control activity in males and
    females, respectively, at either dose level at the end of the study. 
    Brain cholinesterase activity was also inhibited to 76% and 71% of
    the control activity in males and females, respectively, at 125 ppm,
    and to 58% and 52% of the control activity at 250 ppm in males and
    females, respectively.  Similar inhibition was observed after the
    first year of the study.  A slight reduction of less than 9% was
    still found after the 4-week recovery period in erythrocyte and
    brain cholinesterase activity at 250 ppm.  Gross and microscopic
    pathology examinations did not give evidence of any compound-related
    lesions.  The NOAEL in this study was 1.5 ppm, equal to 0.07 mg/kg
    bw/day, based on inhibition of erythrocyte and brain cholinesterase
    at 125 ppm and above (Kirchner  et al., 1991).

    Reproduction studies

    Rats

         Diazinon (purity 94.9%) was administered in the diet to groups
    of rats (Sprague-Dawley CRCD; 30/sex/group) over two parental
    generations (F0, F1) and up to weaning of the F2 pups at
    concentrations of 0, 10, 100 or 500 ppm.  Treatment-related clinical
    symptoms and deaths were observed in a few high-dose females.  They
    consisted of tremors (3/30) and dystocia (2/30) followed by death or
    sacrifice in the F0 generation.  In the F1 generation, a few high-
    dose females showed tremors as only compound-related signs.  Food
    consumption was increased in females of the 500 ppm group in the F0
    generation, whereas in the F1 generation, a dose-related reduction
    of food consumption was observed at 100 and 500 ppm in males only. 

    Body-weight gain was lower in F0 females at 500 ppm during
    gestation.  In the F1 generation, reduced body-weight gain was
    observed at 100 and 500 ppm in males and at 500 ppm in females. 
    There were no treatment-related effects on mating behaviour and the
    reproductive parameters (including mating, fertility, gestation
    indices, number of viable pups, and number of stillborn pups) were
    comparable in control and treatment groups in the F0 generation and
    at the low and intermediate dose level of the F1 generation.  At
    500 ppm, a greater proportion of females showed a prolonged
    gestation duration at both generations.  A decrease in the number of
    pregnancies and viable pups as well as reduced fertility and mating
    indices were observed in high-dose females of the F1 generation.  A
    dose-related reduction in survival of F1 pups was observed at 100
    ppm and 500 ppm and in F2 at 500 ppm.  Weights of F0 pups were
    reduced in the 100 and 500 ppm groups, and in F2 pups at 500 ppm. 
    No treatment-related malformations were found in the pups.  The
    NOAEL in this study was 10 ppm, equivalent to 0.5 mg/kg bw/day,
    based on reduced parental body-weight gain and reduced viability of
    pups and pup weights at 100 ppm and higher (Giknis 1989).

    Special studies on embryotoxicity/teratogenicity

    Mice

         Groups of mice (6 females/dose) were given oral daily doses of
    0, 0.18 or 9 mg/kg bw diazinon throughout gestation.  Treated
    animals gained less weight during gestation compared to control
    animals.  Weight gain of pups born to mothers receiving 9 mg/kg
    bw/day was reduced.  Daily testing for physiological and behavioural
    development of the pups revealed some evidence of retarded
    development among the offspring of high-dose animals (e.g.,
    retardation of eye and ear opening).  Measures of endurance and
    coordination also gave some evidence of impairment (e.g., increased
    rod cling endurance in both groups, reduced rotarod endurance,
    impaired running performance in a maze inclined plane test). 
    Impaired reactions were sometimes observed at both dose levels but
    without a clear dose-effect relationship.  Examination of brain
    tissue of only 8 of a total number of 132 offspring at the high-dose
    level revealed morphological abnormalities in the forebrain.  The
    relationship of these findings to the observed behavioural changes
    is unknown (Spyker & Avery 1977).  The evidence for morphological
    effects of diazinon on the developing brain was considered
    insufficient by an expert (Krinke, 1991).

    Rats 

         In a teratogenicity study in Sprague-Dawley rats at dose levels
    of 0, 15, 50 or 100 mg/kg bw/day administered orally on days 6
    through 15 of gestation, dams at the 100 mg/kg bw/day dose level
    showed a marked decrease in food consumption correlating with weight

    loss at the beginning of the treatment period.  Skeletal assessment
    showed a slightly higher incidence of incomplete ossification at
    different sites in the fetuses at 100 mg/kg bw/day.  Visceral
    examination revealed a dystopia cordis in association with
    hypoplasia of lungs in 1/105 fetuses at 100 mg/kg bw/day.  This
    anomaly has been reported to occur spontaneously in control animals. 
    Because of the single occurrence this anomaly was not considered to
    be due to a direct action of diazinon but to be secondary to
    maternal toxicity (Fritz, 1974).

         In a later study, groups of rats (Charles River Crl. COBS
    CD(SD)(BR); 27 females/group) were treated with doses of diazinon
    (purity 97.4%) at 0, 10, 20 or 100 mg/kg bw/day by gavage during
    gestational days 6 through 15.  The treatment had no effect on the
    mortality of the dams.  During the first half of the dosing period,
    the dams lost weight and food consumption was reduced at 100 mg/kg
    bw/day.  No compound-related clinical signs and no abnormal gross
    pathological findings were observed in the dams.  At 100 mg/kg
    bw/day some reproductive parameters differed from the control values
    but no statistical significance was achieved (e.g., increase in
    number of resorptions, percent pre- and post-implantation loss,
    reduction in number of live fetuses).  On gross observation, 3/262
    (1%) fetuses from 3 litters showed external malformations (single
    occurrences of a umbilical hernia, filament tail, sublingual
    extraneous soft tissue), whereas in the concurrent controls no
    similar effects were observed.  Umbilical hernia and tail
    abnormalities however are reported to be spontaneous malformations
    observed routinely in this rat strain.  Concerning skeletal
    variations, an increased incidence in rudimentary ribs (T-14) was
    observed in all treatment groups attaining statistical significance
    in the high-dose group (5% versus 0%).  Because of the single
    occurrences of the different malformations observed and because the
    malformations also occur in control animals they were considered to
    be a consequence of the marked maternotoxicity at this dose level,
    and not due to a teratogenic effect of the test compound.  The
    increased incidence of the skeletal variation observed at the top
    dose level was considered to be related to maternotoxicity at this
    dose level.  The NOAEL in this study was 20 mg/kg bw/day based on
    maternotoxicity and fetotoxicity at the higher dose level (Infurna &
    Arthur, 1985).

    Rabbits

         Diazinon (purity 89.2%) was administered to groups of pregnant
    rabbits (New Zeeland white; 18-22 females/group) by gavage at dose
    levels of 0, 7, 25 or 100 mg/kg bw/day from days 6-18 of gestation. 
    An increase in maternal mortality was observed at 100 mg/kg bw/day
    (41% vs 0% in all other groups).  Overt clinical signs of maternal
    toxicity at 100 mg/kg bw/day included tremors, convulsions,
    hypoactivity and anorexia.  Reduced body-weight gain was found at
    the highest dose level.  The treatment did not influence the number

    of corpora lutea, number of implantation sites, live fetuses per
    litter or fetal weight.  The incidence of visceral and skeletal
    malformations and variations showed no differences between the
    groups that could be attributed to treatment.  The study therefore
    gave no evidence for an embryotoxic or teratogenic activity of
    diazinon.  The NOAEL in this study was 25 mg/kg bw/day based on
    materno-toxicity at the highest dose level (Harris & Holson, 1981).

    Chickens

         The teratogenic effects of some anticholinesterase insecticides
    (organophosphates and methylcarbamates) on chicken embryos have been
    known for some time.  In a first study, eggs were injected with
    diazinon to explore some of the biochemical variables that might be
    involved in producing micromelia, beak and feather deformities (type
    I signs) in avian embryos that are known to be caused by OP
    insecticides.  The results of this study confirm the assumption that
    a tryptophan deficiency (tryptophan plays an important role in the
    developing embryo) may cause the abnormalities observed (Kushaba-
    Rugaaju & Kitos, 1985).

         Another study was conducted to investigate the involvement of
    cholinergic functions in OP-induced teratogenesis in chick embryos
    by examining the effects of diazinon on the developmental pattern of
    AChE and ChAT activities in hindlimb, wing and brain.  The results
    of this study confirmed that type II teratogenesis (wry neck, short
    neck, arthrogryposis and muscular hypoplasia of legs) may be
    mediated via cholinergic nicotinic receptors.  Cholinergic
    dysfunction including decreased activity of AChE and ChAT was not
    correlated with diazinon-induced type I teratogenesis (micromelia,
    abnormal feathering) (Misawa  et al., 1981).

    Cattle

         As part of a survey to determine the causes of abortion in
    dairy cattle in Wisconsin, the potential role of pesticides was
    examined.  Diazinon in the form of wettable powder was orally
    administered to two pregnant cows at a daily dose level of 6.6 mg/kg
    bw.  The continuous treatment started in the 5th and 6th month of
    pregnancy (abortion commonly affects cows in the 5th to 8th month of
    pregnancy) and was maintained until parturition.  No diazinon
    residues were detected in the tissues examined (fat, liver, kidney)
    nor in milk.  The treatment failed to reveal any abortions (Macklin
    & Ribelin 1971).

    Special studies on genotoxicity

         Diazinon has been adequately tested in a series of genotoxicity
    assays.  The results are summarized in Table 2.

    Special study of effects on the pancreas

         A study was conducted using a canine model to investigate the
    induction of pancreatic ductal hypertension following cholinesterase
    inhibitor intoxication known to be an important triggering mechanism
    in the pathogenesis of acute and chronic pancreatitis.  Diazinon was
    intravenously administered (25 mg/kg bw) to the pancreatic ampulla
    of dogs and the tissue cholinesterase activity of the canine
    pancreatic sphincters was determined.  Two enzymes are responsible
    for the total cholinesterase activity of whole blood: a membrane-
    bound AChE associated with the erythrocyte membrane, and a soluble
    enzyme, pseudocholinesterase or butyrylcholinesterase (BChE) in the
    serum.  In tissues, which also contain the two forms of
    cholinesterase, AChE is important in the regulation of neuromuscular
    activity and parasympathetic ganglion transmission, while the role
    of BChE is unknown.  The observation of the negative correlation
    between serum BChE activity and intraductal pancreatic pressure
    supports the hypothesis that the pancreatic ductal hypertension
    which occurs following cholinesterase inhibitor intoxication is due
    to a selective reduction in pancreatic BChE activity (Dressel  et
     al., 1980).

         The induction of acute pancreatitis by OPs found in dogs was
    confirmed in guinea-pigs but not in cats.  These results may reflect
    species-related differences in the distribution of pancreatic BChE
    (Frick  et al., 1987).

    Special studies on antidotes

         Previous reports with respect to the usefulness of PAM and
    other oxine reactivators against this organophosphate have been
    published (Sanderson & Edson, 1959; Wills, 1959).  A recent study
    was undertaken to provide information on the antidotal effectiveness
    of pyridine-2-aldoxime methochloride (2-PAM) against diazinon
    poisoning in animals.  The administration of atropine (16 mg/ kg bw;
    i.m.) or 2-PAM (30 mg/kg bw; i.v.) alone 10 minutes after poisoning
    rats with doses of 235 mg/kg bw corresponding to the approximate
    oral LD50 or higher provided little or no protection.  Best
    protection was achieved when the oxime was given orally in
    conjunction with atropine (i.m.) or followed by a subsequent dose of
    2-PAM orally or i.v.  Administration of 2-PAM to diazinon-poisoned
    rabbits (1600 mg/kg bw) resulted in reactivation of inhibited blood
    ChE activity concurrent with a decrease in signs of poisoning. 
    Within 2 hours, however, the animals were again weak and ataxic and
    blood ChE showed renewed inhibition.  The authors suggested that
    effective therapy of diazinon intoxication requires repeated doses
    of oxime to maintain effective antidote levels in the body (Harris
     et al., 1969).  In dogs and guinea-pigs, pretreatment with
    atropine protected the animals against diazinon-induced pancreatitis
    (Frick  et al., 1987).

    Special study on delayed neurotoxicity

    Hens

         An oral dose of 28 mg/kg bw/day of diazinon technical (87%
    purity) was administered to a group of 18 hens (the target dose of
    13 mg/kg bw/day as the approximate LD50 was doubled due to a
    preparation error).  The schedule to protect the hens from acute
    cholinergic effects of diazinon consisted of a 10 mg/kg bw atropine
    pretreatment (i.m.).  At the time of diazinon dosing, 2-PAM at an
    i.m. dose of 50 mg/kg bw was administered.  Post-treatment consisted
    of concurrent doses of atropine and 2-PAM one and five hours
    following dosing.  Since there were no neurotoxic responses in the
    test group in the three weeks following the treatment they were
    again treated with 13 mg/kg bw of diazinon on day 21.  One test
    group hen was found dead on day 5 after the first dosing, and one
    hen six hours after the second treatment.  One hen exhibited a
    slight unsteadiness in walking only on day 41.  No neurotoxic signs
    became apparent during the three-week observation period after the
    second treatment.  Histopathological examination revealed no lesions
    in the brain, spinal cord or peripheral nerves in diazinon-treated
    animals, whereas animals of the positive control (TOCP treatment)
    showed multiple lesions (axonal degeneration) consistent with
    peripheral neuropathy (Jenkins, 1988).

    Observations in humans

         Numerous reports of intentional and accidental intake of
    diazinon and other OPs have been published describing the clinical
    manifestations of organophosphate toxicity and the usefulness of
    erythrocyte and serum cholinesterase activity assays for diagnosis
    as well as the efficacy of supportive and specific therapies
    (Kabrawala  et al., 1965; Payot, 1966; Banerjee, 1967; Gupta &
    Patel, 1968; Zwiener & Ginsburg, 1988).

         A case of acute diazinon poisoning complicated by pericarditis
    and pneumonia followed by recovery has been reported.  The
    intoxication caused the occurrence of cyanosis, tracheobronchial
    congestion, pulmonary edema and pneumonia.  The treatment included
    the intramuscular injection of atropine (Banerjee, 1967).

         Another complication reported following accidental ingestion of
    diazinon consisted of severe pancreatitis and a pseudocyst (Dressel
     et al., 1979).  The induction of pancreatitis was reproduced in
    dogs treated intravenously with a dose of 5 mg/kg bw diazinon. 
    Pancreatitis may be the result of hypersecretion and ductal
    obstruction (Dressel  et al., 1980).


        Table 2.  Results of genotoxicity assays on diazinon
                                                                                                                                              
    Test system         Test object                   Concentration/dose       Purity               Results            Reference
                                                                                         Non-activated    Activated
                                                                                                                                              

     In vitro

    Ames test           S. typhimurium                313-5000 µg/0.1 ml       88.0%     negative         negative     Geleick & Arni, 1990
                        TA 98, 100, 1535, 1537        DMSO
                        E. coli WP2uvrA

    Ames test           S. typhimurium                in DMSO >50-1000         ?         negative         negative     Marshall et al., 1976
                        TA 1535, 1536, 1537, 1538     µg/plate

    Mouse lymphoma      Mouse lymphoma cell           1. 6 to 60 µg/ml with    97.2%     negative         negative     Dollenmeier & Müller, 
    assay               L5178Y/TK+/-                  activation                                                       1986 
                                                      2. 12 to 120 µg/ml 
                                                      without activation

    Mouse lymphoma      Mouse lymphoma cell           up to 100 µg/ml          ?         positive         positive     McGregor et al., 1989
    assay               L5178Y TK+/-

    Sister chromatid    Chinese hamster cells         10, 20 and 40 µg/ml      99.2%     negative                      Chen et al., 1981
    exchange study      (V79)                         99.2% in DMSO

    Chromosomal         Chinese hamster lung          0.1 mg/ml                ?         cytotoxic        positive     Matsuoka et al., 1979
    aberration test     cells

    Sister chromatid    Human lymphoid cells          0.02, 0.2, 2.0 and       ?         negative         negative1    Sobti et al., 1982
    exchange study      (LAZ-007)                     200 µg/ml
                                                      in Ethanol (< 0.1%)

    Sister chromatid    Human lymphoid cells          12.5, 25, 50, 100 and    87.5%     negative         negative     Strasser & Arni, 1988
    exchange study      (CCL-156)                     200 µg/ml in DMSO

                                                                                                                                              

    Table 2 (contd)
                                                                                                                                              
    Test system         Test object                   Concentration/dose       Purity               Results            Reference
                                                                                         Non-activated    Activated
                                                                                                                                              

    Sister chromatid    Whole blood human             1. 0.0668 to 2000 µg/ml  88.0%     equivocal        equivocal2   Murli & Haworth, 1990a
    exchange study      lymphocytes                   in DMSO (ħ activation)
                                                      2. 0.668 to 20 µg/ml 
                                                      (non-activation)
                                                      3. 2-66.8 µg/ml 
                                                      (activated)

    Autoradiographic    Rat hepatocytes               1.1 to 120 µg/ml in      88.0%     negative                      Hertner & Arni, 1990
    DNA repair test                                   DMSO

     In vivo

    Micronucleus test   Mouse                         1. 120 mg/kg bw oral     87.5%     negative                      Ceresa, 1988
    in  vivo                                          2. 30, 60, and 
                                                      120 mg/kg bw oral

    Dominant lethal     Mouse                         oral dose of 14 and 45   95%       negative                      Fritz, 1975
    study                                             mg/kg bw 

    Chromosome studies  Mouse                         a) daily oral doses of   ?         negative                      a) Hool & Müller, 1981c
    in male germinal    a) spermatogonia              10.5, 21 and 63 mg/kg                                            b) Hool & Müller, 1981b
    epithelium          b) spermatocytes              bw for five days, or 
                                                      b) 5 treatments with  
                                                      the same doses over 
                                                      a period of 10 days

    Sister chromatid    Bone marrow cells             single oral doses of     88.0%     negative                      Murli & Haworth, 1990b
    exchange study      of mice                       10, 50 and 100 
    in vivo                                           mg/kg bw

                                                                                                                                              

    Table 2 (contd)
                                                                                                                                              
    Test system         Test object                   Concentration/dose       Purity               Results            Reference
                                                                                         Non-activated    Activated
                                                                                                                                              

    Sister chromatid    Chinese hamster bone          oral gavage of 6.5       ?         negative                      Hool & Müller, 1981a
    exchange study      marrow cell                   to 26 mg/kg bw

    Nucleus anomaly     Chinese hamster bone          oral gavage of           ?         negative                      Hool & Müller, 1981d 
    test                marrow cells                  6.5, 13 and 26 mg/kg 
                                                      bw/day for two days

                                                                                                                                              

    1    Cyotoxicity at a concentration of 20 µg/ml.  The increased frequency of sister chromatid exchanges at 20 µg/ml with
         metabolic activation did not show a doubling of the control frequency and was therefore not considered positive.
    2    Two independent trials: Cytotoxicity at concentrations of 66.8 µg/ml (with activation) respectively.  Increases in the SCE
         frequency (just doubling) observed only in the first assay without metabolic activation at dose levels of 0.668 µg/ml to
         20 µg/ml, but without a dose-relationship.  Increases observed after activation in both trials did not show doubling and again
         no dose-response.  Thus the results of these studies are not considered positive.
    

         A study of 60 poisoning cases with diazinon has been reported. 
    The most common clinical manifestations were vomiting, giddiness,
    constricted pupils and signs of bronchoconstriction with pulmonary
    congestion.  The amount of poison ingested varied from 4 ml to 15 ml
    with an average of 7.5 ml (% active ingredient not specified in
    publication).  This was ingested by 55 patients with suicidal
    intention, whereas in 5 patients the compound was taken
    accidentally.  Atropine injections were administered repeatedly (up
    to a total dose of 22.4 g over 42 hours).  Five patients died in
    spite of intensive atropine therapy initiated more than 8 hours
    after ingestion.  Other cases who had ingested the same amount of
    poison as the fatal cases received treatment within three hours of
    ingestion.  These findings emphasize the importance of early
    treatment in diazinon poisoning (Gupta & Patel, 1968).  In addition,
    these results are in agreement with an earlier observation that the
    combination of diazinon with cholinesterase occurs in two stages, an
    early reversible stage and a late irreversible stage (Grob, 1956).

         In another study, cases of organophosphate and carbamate
    poisoning in 37 infants and children were reported, only 5 of which
    were associated with diazinon.  Miosis, excessive salivation, muscle
    weakness, respiratory distress, lethargy and tachycardia were the
    most common clinical findings.  Erythrocyte cholinesterase
    activities were determined from 24 patients showing erythrocyte
    cholinesterase activities that were less than 50% of the lower limit
    of the normal range.  There were no differences between the
    erythrocyte and serum cholinesterase activity in 20/24 patients from
    whom both tests were obtained, whereas in the remaining 4 cases
    either the erythrocyte or the serum activity was decreased.  A
    combined atropine/pralidoxime therapy is recommended in case of
    organophosphate toxicity.  Although the recommended dose for
    atropine in infants is 0.01-0.02 mg/kg bw, the dose is generally
    insufficient for treatment of signs and symptoms secondary to
    organophosphate poisoning (Zwiener & Ginsburg, 1988).

         Neurobehavioural effects of short-term, low-level exposure to
    diazinon were investigated in 99 pest control workers.  A computer
    assisted neuro-behavioural test battery (including attention,
    vigilance, hand-eye coordination, visual perception, verbal ability)
    was used before and after their work shift.  The diazinon metabolite
    diethyl-thiophosphate (DETP) was measured in urine samples collected
    from 46 diazinon applicators and 56 non-applicators.  Post-shift
    DETP values were 24 and 3 ppb for applicators and non-applicators,
    respectively.  The study failed to demonstrate any behavioral
    effects of diazinon under the conditions of this study (Maizlish  et
     al., 1987).

         The results of the following old study have been reported in an
    earlier monograph (Annex I, reference 7).  Because of certain
    inaccuracies in that monograph, the study was reviewed again and
    summarized below.

         A subacute oral toxicity study was conducted in four male
    volunteers.  Diazinon (different batches, purity 95.4-95.7%) was
    administered in capsules at dose levels of 2-2.5 mg per day per
    person, equal to a dose of 0.025 mg/kg bw/day.  The test period
    lasted 42 days with an interruption in treatment from the 5th to
    10th day in two volunteers and for 34 consecutive days in the other
    two volunteers.  Plasma cholinesterase activity was markedly
    depressed the first 6 days of treatment in 2/4 subjects (no plasma
    cholinesterase activity measurable).  Therefore treatment was
    interrupted for 6 days to enable recovery.  Subsequent treatment at
    the same dose level did not reveal inhibitory effects on plasma
    cholinesterase.  The fluctuations observed during the treatment
    period were similar to those observed during the pre-test period. 
    In no instance was the erythrocyte acetylcholinesterase depressed
    compared to the pre-test values.  Other parameters investigated
    included haematology and blood chemistry, urinalyses and
    symptomatology.  No changes were observed that could be attributed
    to the treatment.  The NOAEL in this study was 0.025 mg/kg bw/day
    based on transitory depression of plasma cholinesterase activity as
    the only effect observed at this dose level (Payot, 1966).

    COMMENTS

         Following oral administration to rats, diazinon was almost
    completely absorbed and eliminated, mainly in the urine.

         The main degradative pathway includes the oxidase/hydrolase-
    mediated cleavage of the ester bond leading to the pyrimidinol
    derivative 2-isopropyl-6-methyl-4(1H)-pyrimidinone, which is further
    oxidized to more polar metabolites.

         Diazinon has moderate acute oral toxicity to mice and rats. 
    The clinical signs observed were consistent with cholinesterase
    inhibition and included sedation, tremors, convulsions and ataxia. 
    It has been classified by WHO as moderately hazardous.

         In an oral 90-day feeding study in rats at dietary
    concentrations of 0, 0.5, 5, 250 or 2500 ppm, the NOAEL was 5 ppm
    (equal to 0.4 mg/kg bw/day), based on erythrocyte and brain
    cholinesterase inhibition at 250 ppm and higher.

         In short-term studies in dogs, diazinon was administered at
    dietary concentrations of 0, 0.1, 0.5, 150 or 300 ppm for either 90
    days or 52 weeks.  In both studies, the NOAEL was 0.5 ppm, equal to
    0.02 mg/kg bw/day based on erythrocyte and brain cholinesterase
    inhibition at 150 ppm and above.

         In a carcinogenicity study in mice, diazinon was administered
    at dietary concentrations of 0, 100 or 200 ppm over 103 weeks. 
    There was no evidence of carcinogenicity.

         In a carcinogenicity study in rats diazinon was administered at
    dietary concentrations of 0, 400 or 800 ppm for 103 weeks.  There
    was no evidence of carcinogenicity.

         In a long-term toxicity/carcinogenicity study, rats were
    maintained on a diet containing diazinon at concentrations of 0,
    0.1, 1.5, 125 or 250 ppm for up to 99 weeks.  The NOAEL was 1.5 ppm,
    equal to 0.07 mg/kg bw/day, based on inhibition of erythrocyte and
    brain cholinesterase at 125 ppm and above.  There was no evidence of
    carcinogenicity.

         A multigeneration study was conducted in rats using dietary
    concentrations of 0, 10, 100 or 500 ppm.  The NOAEL was 10 ppm
    (equivalent to 0.5 mg/kg bw/day), based on a reduction in parental
    body-weight gain in the F1 generation and a reduced survival rate
    and reduced body weight of F1 pups at 100 ppm.

         In a teratogenicity study in rats, diazinon was orally
    administered at dose levels of 0, 10, 20 or 100 mg/kg bw/day. 
    Maternal toxicity, indicated by weight loss correlating with reduced

    food consumption, became evident at 100 mg/kg bw/day.  Effects on
    the fetuses at this dose level consisted of retarded ossification
    and an increased incidence of rudimentary ribs.  The NOAEL was 20
    mg/kg bw/day based on maternotoxicity and fetotoxicity.  There was
    no evidence of teratogenicity.

         A teratogenicity study in rabbits conducted with oral dose
    levels of 0, 7, 25 or 100 mg/kg bw/day revealed clinical signs of
    maternotoxicity, increased mortality and reduced body-weight gain at
    100 mg/kg bw/day.  The NOAEL was 25 mg/kg bw/day.  There was no
    evidence of teratogenicity.

         A neurotoxicity study performed with hens treated at dose
    levels of 13 or 28 mg/kg bw/day (protected by atropine pre-
    treatment) did not reveal evidence of delayed neurotoxicity.

         Diazinon has been adequately tested in a series of genotoxicity
    assays.  Chromosomal aberrations were induced in cultured mammalian
    cells, but there were no other indications of genotoxicity.  The
    Meeting concluded that diazinon was not genotoxic.

         Diazinon was evaluated in four human male volunteers who
    received 0.025 mg/kg bw/day of diazinon in capsules for 34-36 days. 
    There were no consistent treatment-related effects on plasma or
    erythrocyte cholinesterase activity, blood chemistry or urinalysis. 
    No clinical effects were reported.  The NOAEL was 0.025 mg/kg
    bw/day.

         The ADI of 0-0.002 mg/kg bw, which was based on the NOAEL of
    0.025 mg/kg bw/day in the study in humans using a 10-fold safety
    factor, was maintained.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat:      5 ppm, equal to 0.4 mg/kg bw/day (90-day study)
                   1.5 ppm, equal to 0.07 mg/kg bw/day (99-week study)
                   10 ppm, equivalent to 0.5 mg/kg bw/day 
                   (reproduction study)
                   20 mg/kg bw/day (maternotoxicity in teratogenicity
                   study)

         Rabbit:   25 mg/kg bw/day (maternotoxicity in teratogenicity
                   study)

         Dog:      0.5 ppm, equal to 0.02 mg/kg bw/day (one-year study)

         Human:    0.025 mg/kg bw/day (34-36-day study)

    Estimate of acceptable daily intake for humans

                   0-0.002 mg/kg bw

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

              Further observations in humans.

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    See Also:
       Toxicological Abbreviations
       Diazinon (EHC 198, 1998)
       Diazinon (ICSC)
       Diazinon (PDS)
       Diazinon (FAO Meeting Report PL/1965/10/1)
       Diazinon (FAO/PL:CP/15)
       Diazinon (FAO/PL:1967/M/11/1)
       Diazinon (FAO/PL:1968/M/9/1)
       Diazinon (AGP:1970/M/12/1)
       Diazinon (WHO Pesticide Residues Series 5)
       Diazinon (Pesticide residues in food: 1979 evaluations)
       Diazinon (JMPR Evaluations 2001 Part II Toxicological)