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    PESTICIDE RESIDUES IN FOOD - 1997


    Sponsored jointly by FAO and WHO
    with the support of the International Programme
    on Chemical Safety (IPCS)




    TOXICOLOGICAL AND ENVIRONMENTAL
    EVALUATIONS 1994




    Joint meeting of the
    FAO Panel of Experts on Pesticide Residues
    in Food and the Environment
    and the
    WHO Core Assessment Group 

    Lyon 22 September - 1 October 1997



    The summaries and evaluations contained in this book are, in most
    cases, based on unpublished proprietary data submitted for the purpose
    of the JMPR assessment. A registration authority should not grant a
    registration on the basis of an evaluation unless it has first
    received authorization for such use from the owner who submitted the
    data for JMPR review or has received the data on which the summaries
    are based, either from the owner of the data or from a second party
    that has obtained permission from the owner of the data for this
    purpose.



    MALATHION

    First draft prepared by
    T.C. Marrs
    Medical Toxicology and Environmental Health
    Department of Health, London, United Kingdom

         Explanation 
         Evaluation for acceptable daily intake 
              Biochemical aspects 
                   Absorption, distribution, and excretion 
                   Biotransformation
                   Effects on enzymes and other biochemical parameters 
                        Cholinesterases
                        Other enzyme systems
                        Interactions with other organophosphates
              Toxicological studies
                   Acute toxicity
                   Short-term toxicity
                   Long-term toxicity and carcinogenicity 
                   Genotoxicity
                   Reproductive toxicity
                        Multigeneration reproductive toxicity
                        Developmental toxicity
                   Special studies
                        Dermal and ocular irritation and dermal
                        sensitization 
                        Macrophage and mast cell function
                        Ocular function
                        Neurotoxicity
                        Antidotes 
              Observations in humans 
         Comments
         Toxicological evaluation 
         References 

    Explanation

         Malathion was evaluated by the JMPR in 1963, 1965, and 1966
    (Annex 1, references 2, 4, and 6). An ADI of 0-0.02 mg/kg bw was
    established in 1963, which was confirmed in 1965 and 1966. It was
    evaluated at the present Meeting within the CCPR periodic review
    programme.

         Malathion is  S-1,2-bis(ethoxycarbonyl)ethyl  O,O-dimethyl
    phosphorodithioate. It is likely that the results of earlier
    toxicological studies on malathion have been substantially affected by
    impurities. Of particular interest are isomalathion
    [ S-1,2-bis(ethoxycarbonyl)ethyl  O,S-dimethyl phosphorodithioate]
    and various trialkyl phosphorothioates [for reviews, see Aldridge et
    al. (1985) and Dinsdale (1992)]. These compounds are notable for their

    pulmonary toxicity. Furthermore, isomalathion has a greater than
    additive effect when administered with malathion, probably due to
    carboxylesterase inhibition (Ryan & Fukuto, 1984). In fact,
    isomalathion appears to be the major impurity of malathion and affects
    the LD50 of the commercial formulation.  O,O,S-Trimethyl
    phosphorothioate and  O,S,S-trimethyl phosphorothioate produce
    disorders of blood clotting (Keadtisuke et al., 1990), and
     O,O,S-trimethyl phosphorothioate produces an unusual neurotoxic
    syndrome with hypophagia, weight loss, and hypothermia (Ohtako et al.,
    1995).

         After an epidemic of malathion poisoning among spraymen in
    Pakistan (Baker et al., 1978), WHO issued specifications for malathion
    water-dispersible powders, which required that a 50% powder contain no
    more than 0.9% isomalathion after storage at 54 ¡C for six days (Miles
    et al., 1979; WHO, 1985). Subsequently, major manufacturers, under the
    auspices of FAO, adopted a code of conduct which requires that, 
     inter alia, the active ingredient and co-formulant of commericial
    formulation be the same as those tested toxicologically (FAO, 1986). 

         It is likely that esterase-inhibitory activity attributed to
    technical-grade malathion is due largely to the action of malaoxon
    (WHO, 1986).

    Evaluation for acceptable daily intake

    1.  Biochemical aspects

     (a)  Absorption, distribution, and excretion

         The disposition of 14C-malathion (purity, > 98%; specific
    activity; 90 µCi/mg (3.3 MBq/mg)), labelled at the carbonyl carbons of
    the ethoxycarbonyl groups, was studied by Reddy et al. (1989). After a
    preliminary study, 14C-malathion in corn oil was administered by
    gavage as single doses of 40 or 800 mg/kg bw to groups of five male
    and five female Sprague-Dawley (Crl:CD BR) rats. Disposition was also
    assessed after administration of oral doses of unlabelled malathion
    (purity, 94.6%) at 40 mg/kg bw per day for 15 days, followed by a 16th
    dose of 14C-malathion. In the preliminary study, very little of the
    radiolabel appeared in expired air, and most was eliminated within 72
    h; consequently, in the main study, the animals were killed at 72 h.
    Malathion was rapidly absorbed, biotransformed, and excreted,
    predominantly in the urine but also in the faeces. After the low dose,
    84% appeared in the urine of males and 88% in that of females within
    72 h, mostly within 12 h: faecal elimination was 11 and 5.9% in males
    and females, respectively. Less than 1% of the administered dose was
    recovered in the tissues. At the high dose, urinary excretion was 76%
    for the males and 85% for the females; faecal elimination was 14 and
    6.6%, respectively. Low concentrations were present in tissues at 72
    h. After the repeated doses, 85 and 88% of the label was excreted in
    the urine within 72 h, mostly within the first 12 h, and faecal
    elimination was 6.8% in males and 5.8% in females. Less than 1% of the
    dose was present in the tissues.

         Malathion, either of 94.6% purity or a 50% emulsifiable
    concentrate, was labelled with 14C in one methoxy group and given
    orally to male Sprague-Dawley albino rats at a dose of 280 mg/kg
    active ingrdient (approximately one-tenth of the LD50). More than 90%
    of the dose was excreted in the urine within 24 h; the rest of the
    label was detected in the faeces, intestines, liver, and kidney, in
    descending order of concentration. The disposition of the pure
    malathion and the 50% emulsifiable concentrate was not significantly
    different (Abou Zeid et al., 1993).

         The toxicokinetics of malathion was studied by Garcia-Repetto et
    al. (1995) after oral administration of a dose of 467 mg/kg bw (stated
    to be one-third of the LD50) to male albino Wistar rats. A two-
    compartment model was discerned, the central compartment being blood,
    adipose tissue, and muscle and the peripheral compartment, brain and
    liver. The half-life in blood was 1.4 ± 0.25 days. In a fatal case of
    malathion poisoning, malathion and the mono- and dicarboxylic acids
    were found in cardiac blood and tissues, malaoxon being found
    additionally in most tissues (Morgade & Barquet, 1982).

     (b)  Biotransformation

         In the study of Reddy et al. (1989) cited above, the metabolites
    of malathion were studied by high-perfomance liquid chromatography and
    gas chromatography-mass spectrometry. 14C-Malathion was excreted in
    urine and faeces as the a and b monocarboxylic acids and the
    dicarboxylic acid of malathion. Minor metabolites were the oxon of
    malathion (malaoxon),  O,O-dimethylphosphorodithioic acid,
    2-mercaptosuccinic acid, fumaric acid, monoethyl fumarate,
     O,O-dimethylphosphorothioic acid, and desmethylmalathion. Figure 1
    shows the proposed pathway for the metabolism of malathion in rats.

     (c)  Effects on enzymes and other biochemical parameters

     (i)  Cholinesterases

         Groups of 27 male and 27 female Sprague-Dawley Crl:CD:BR rats
    were given malathion (purity, 96.4%) by gavage in corn oil at doses of
    0, 500, 1000, or 2000 mg/kg bw; 20 animals of each sex were used to
    measure cholinesterase activity, and seven of each sex for
    determination of neuropathological effects. Viability, clinical signs,
    body weights, and the results of a functional observational battery of
    tests and locomotor activity were recorded before treatment, 15 min
    after treatment, and on days 7 and 14 in seven animals of each sex per
    dose of those reserved for neuropathology and five of each sex at each
    dose of those destined for cholinesterase measurements. Cholinesterase
    activity was determined in plasma, erythrocytes, and brain regions in
    five animals of each sex per group before the start of the study, 15
    min after treatment, and on day 15. Similar measurements were made on
    day 7, but as one male was killed  in extremis, only four remained at
    this time. Treatment-related clinical signs consisting of salivation
    and/or anogenital staining occurred after one or two days of treatment
    in all groups. Additionally reduced hindlimb extensor strength was

    FIGURE 1

    seen in one male at the highest dose and decreased ambulatory and
    motor activity counts in males at this dose on day 0. These males also
    showed a > 20% reduction in plasma cholinesterase activity in
    comparison with controls at day 7; although no reduction was seen at
    1000 mg/kg bw, a marginal reduction was seen at 500 mg/kg bw. No
    reductions were seen at other times. In females, reductions > 20%
    were seen at both 500 and 2000 mg/kg bw at day 7 and at the latter
    dose at day 15. Erythrocyte acetylcholinesterase activity was reduced
    by > 20% in the males at the highest dose at day 7, while in females
    it was reduced by > 20% at day 0 (500 and 2000 mg/kg bw), day 7 (1000
    and 2000 mg/kg bw) and day 15 (2000 mg/kg bw only). No consistent
    biologically significant depressions in brain acetylcholinesterase
    activity were seen, although there were 10-20% decreases in activity
    in comparison with concurrent controls, mainly in the group at the
    high dose. There were no treatment-related neuropathological lesions.
    There was no NOAEL, as clinical signs occurred in all groups (Lamb,
    1994a). 

         Malathion (purity, 96.4%) was given to groups of 25 male and 25
    female Sprague-Dawley Crl:CD:BR rats at dietary concentrations of 0,
    50, 5000, or 20 000 ppm (equal to 0, 4, 350, or 1500 mg/kg bw per day
    in males and 0, 4, 400, or 1600 mg/kg bw per day in females) for
    13 weeks. Clinical signs, body weight, and food consumption were
    recorded, a functional observational battery of tests was carried out,
    and locomotor activity was evaluated. Plasma, erythrocyte, and
    regional brain cholinesterase activities were measured in five animals
    of each sex per dose before treatment, at weeks 3 and 7, and at the
    end of the study. Tissues from the remaining five animals in each
    group were perfused  in situ, and neuropathological examinations were
    carried out on the brains of the controls and animals at the high
    dose. All animals survived to the end of the study. 

         Anogenital staining was observed in rats at the high dose, and
    body-weight gain and food consumption were reduced in comparison with
    controls. No treatment-related effects were seen in functional and
    locomotor evaluations. Plasma cholinesterase activity was > 20% lower
    than in concurrent controls in males at 20 000 ppm at all times after
    the start of treatment, while the activity in rats at 5000 ppm was
    reduced by 10-20%; erythrocyte acetylcholinesterase activity was
    reduced by > 20% at all times in rats at doses > 5000 ppm. In the
    females, reductions of > 20% were seen in plasma cholinesterase at
    5000 ppm at week 7 only and at 20 000 ppm at all three times (all by
    comparison with concurrent controls). Reductions in erythrocyte
    acetylcholinesterase activity of > 20 % were seen at all times in
    females at 5000 and 20 000 ppm. Regional brain acetylcholinesterase
    activity was very variable; significant depressions in activity were
    seen only in rats at the high dose. Thus, significant depressions were
    seen in the olfactory lobe (by 34%) and midbrain (by 24%) and a
    marginally significant depression (18%) in the brain stem of males at
    week 13; in the cerebral cortex, a 26% depression in activity was seen
    at week 7 only. No clinically or biologically significant depression
    in activity was seen in the hippocampus or cerebellum of males. In
    females, depressed brain acetylcholinesterase activity was observed

    more often and frequently to a greater extent than in the males.
    Depressed activity in comparison with concurrent controls was seen in
    the olfactory lobe at 3 (31%), 7 (27%), and 13 weeks (50%) and in the
    brainstem at 13 weeks (36%), less depression in activity being seen at
    the other times. In the midbrain, depressed activity was seen at 7
    (34%) and 13 weeks (40%). In the cerebral cortex, depressions were
    seen at 3 (32%), 7 (40%), and 13 weeks (53%). In the hippocampus,
    depressed activity occurred at all times, by 44% at 3 weeks, 38% at 7
    weeks, and 47% at 13 weeks. In the cerebellum, depressions of 20% at 3
    weeks and 32% at 13 weeks were seen. No effects were observed on the
    absolute or relative weights of the brain or brain regions, and no
    neuropathological abnormalities were observed. The NOAEL was 5000 ppm,
    equal to 350 mg/kg bw per day, on the basis of the occurrence of
    statistically and biologically significant inhibition of brain
    acetylcholinesterase activity at the highest dose (Lamb, 1994b). 

         Malaoxon is a much more powerful anticholinesterase than
    malathion, and very pure samples of the latter have little activity
    (WHO, 1986). Thus, the IC50 values for cholinesterase inhibition in
    17-day-old aggregate cultures of rat neural cells were > 12 × 10-4
    mol/L for malathion and 2.8 × 10-4 mol/L for malaoxon (Segal &
    Federoff, 1989). Malaoxon produces a dimethylphosphorylated
    cholinesterase, however, which rapidly undergoes spontaneous
    reactivation, as shown  ex vivo in the blood of malaoxon-poisoned
    rats, rabbits, dogs, and monkeys (Abraham & Edery, 1976).

         Abou Zeid et al. (1993) showed that there was faster recovery of
    serum cholinesterase activity in Sprague-Dawley rats after dermal
    application of pure malathion than of the 50% emulsifiable
    concentrate.

         Ward et al. (1993) reported a correlation between the
    anticholinesterase activity of a series of organophosphates, including
    malathion and malaoxon, and their ability to compete with agonist
    binding to muscarinic receptors.

     (ii)  Other enzyme systems

         When rat microsomal suspensions were incubated with 4 mmol/L
    malathion  in vitro, the release of ß-glucuronidase was inhibited
    (Lechener & Abdel-Rahman, 1985).

     (iii)  Interactions with other organophosphates

         Feeding Holtzman rats with fenchlorphos potentiated the effect on
    erythrocyte or brain acetylcholinesterase activity of a single
    intraperitoneal challenge with malathion at 200 mg/kg bw (Murphy &
    Cheever, 1968). The combined effect on dioxathion and malathion was
    more or less than additive, depending on the doses used. Malathion
    acts synergistically with many other organophosphates, such as
    ethyl- para-nitrophenyl thionobenzenephosphonate (Frawley et al.,

    1957), at substantial doses. The LD50 of malathion is markedly
    reduced by co-administration of tri- ortho-tolylphosphate (Murphy et
    al., 1959).

    2.  Toxicological studies

     (a)  Acute toxicity

         It is likely that the results of earlier studies on malathion
    were substantially affected by impurities. The LD50 values for these
    impurities in rats after oral administration are: isomalathion, 89-120
    mg/kg bw,  O,O,S-trimethylphosphorodithioate, 450-660 mg/kg bw,
     O,S,S-trimethyl-phosphorodithioate, 26-110 mg/kg bw, and
     O,O,S-trimethylphophorothioate, 47-260 mg/kg bw (Aldridge et al.,
    1979).

         The results of studies on the acute toxicity of malathion are
    given in Table 1; those on malaoxon are summarized in Table 2.

     (b)  Short-term toxicity

     Rats

         Malathion (purity, 96.4%) was administered in the diet to groups
    of five male and five female albino Fischer (CDF:F-344/CrlBR) rats for
    29 or 30 days at concentrations of 0, 50, 100, 500, 10 000, or 20 000
    ppm, equal to 0, 5.1, 10, 52, 1000, or 2000 mg/kg bw per day for males
    and 0, 5.7, 12, 58, 1100, or 2200 mg/kg bw per day for females. The
    animals were observed weekly for body weight and food consumption.
    Ophthalmological, haematological, and clinical chemical examinations,
    including plasma and erythrocyte cholinesterase activity, were
    undertaken before treatment and at termination of the study; brain
    acetylcholinesterase activity was measured at termination. Animals
    were autopsied at the end of treatment, and selected organs were
    examined and weighed; microscopic examination of organs was carried
    out only in the controls and rats at 20 000 ppm. 

         No deaths occurred during the study, adverse clinical signs were
    not seen, and no abnormalities were present on ophthalmological or
    haematological examination. A number of abnormal biochemical variables
    were noted, including cholinesterase activity. That in plasma was
    decreased by > 20% in animals at the two highest doses in comparison
    with concurrent controls, while erythrocyte acetylcholinesterase
    activity was decreased in males at 10 000 ppm (by 17%) and 20 000 ppm
    (by 16%) and only slightly in females. At 10 000 ppm, brain
    acetylcholinesterase activity was depressed at termination by 11% in
    males and 17% in females, while at 20 000 ppm there was a 26% decrease
    in males and 28% in females. Differences were seen between treated
    groups in total protein and albumin concentrations, and a significant
    decrease in alkaline phosphatase activity was seen in animals at the
    two highest doses. Animals at 20 000 ppm had a significant decrease in
    weight gain in comparison with the control group, while food
    consumption was decreased only during week 1. The relative and


        Table 1.  Acute toxicity of malathion

                                                                                                                                             

    Species        Strain             Sex     Route                      LD50 and 95% CI, ±SEM,          Purity     Reference
                                                                         or range (mg/kg bw, unless      (%)
                                                                         otherwise stated) or LC50
                                                                                                                                             

    Mouse          Swiss white        F       Oral                       6100                            > 95       Toia et al. (1980)

    Mouse          Swiss-Webster      M,F     Intraperitoneal            985                             NR         Menzer & Best (1968)
                                                                         954-1018

    Rate           Wistar             M       Oral                       2800                            NR         Dauterman & Main (1966)
                                                                         2660-3110

    Rat            Osborne-Mendel     NR      Oral                       1400 ± 100                      98         Frawley (1957)

    Rat            Sherman            M       Oral                       1375                            NR         Gaines (1969)
                                                                         1206-1568
                                      F                                  1000
                                                                         885-1130

    Rat            Wistar             M,F     Oral                       1580                            92.2       Pellegrini & Santi (1972)

    Rat            Wistar             M,F     Oral                       8000                            98.2       Pellegrini & Santi (1972)

    Rat            Wistar             M       Oral (laboratory chow)     1090 ± 83                       95         Boyd & Tanikella (1969)
                                              Oral (26% casein)          1401 ± 99
                                              Oral (3.5% casein)         5993 ± 138

    Rat            Sprague-Dawley     M,F     Oral                       5000 ± 385                      NR         Terrell et al. (1978)

    Rat            Sprague-Dawley     M       Oral                       3800 (3040-4750)                NR         Cooper & Terrell (1979a)

    Rat            Lac:P                      Oral                       10 700 (9300-12 300)            99.7       Aldridge et al. (1979)

    Rat            Sprague-Dawley     F       Oral                       4400 (2533-8228)                NR         Cooper & Terrell (1979a)

    Table 1.  (continued)

                                                                                                                                             

    Species        Strain             Sex     Route                      LD50 and 95% CI, ±SEM,          Purity     Reference
                                                                         or range (mg/kg bw, unless      (%)
                                                                         otherwise stated) or LC50
                                                                                                                                             

    Rat            Sprague-Dawley     M       Oral                       3200 (2651-3862)                NR         Cooper & Terrell (1979b)
                                      F                                  3700 (2221-6164)

    Rat            CD Sprague-        M       Oral                       5400 (4100-6900)                96-98      Kynoch (1985a)
                   Dawley-derived     F                                  5700 (4300-7800)

    Rat            Albino Crl:CD      M       Oral                       6156 (4665-8123)                96.8       Fischer (1991)
                   (SD)BR             F                                  4061 (3078-5359)

    Rat            Wistar             M       Oral                       734                             NR         Jokanovic & Maksimovic
                                      F                                                                             (1995)

    Rat            HSD Sprague-       M       Oral                       8210 (6518-10 342)              99.1       Kuhn (1996)
                   Dawley             F                                  8239 (6239-10 881)

    Rat            Sprague-Dawley     M       Intraperitoneal            1100                            NR         Murphy et al. (1959)

    Rat            Sherman            M,F     Derman (57%                > 44 444                        NR         Gaines (1969)
                                              emulsifiable
                                              concentrate)

    Rat            CD Sprague-        M,F     Derman                     > 2000                          96-98      Kynoch (1985b)
                   Dawley-derived

    Rat            Albino Wistar      M,F     Inhalation (4 h)           > 5.2 mg/L                      96-98      Jackosn et al. (1986)

    Rabbit         New Zealand        M,F     Derman                     8.79 ± 0.48                     NR         Imlay et al. (1978)
                   albino

    Hamster        Syrian             F       Intraperitoneal (30%       24 00                           NR         Dzwonkowska &
                                              commercial                                                            Hubner (1986)
                                              preparation)

    Table 1.  (continued)

                                                                                                                                             

    Species        Strain             Sex     Route                      LD50 and 95% CI, ±SEM,          Purity     Reference
                                                                         or range (mg/kg bw, unless      (%)
                                                                         otherwise stated) or LC50
                                                                                                                                             

    Dog            Mongrel            NR      Oral                       > 4000                          98         Frawley (1957)

    Dog            Mongrel            M       Intraperitoneal            1.517 ml/kg bw                  95         Guiti & Sadoghi (1969)
                                                                         0.77-2.25

    Buffalo        Indian (Bubalus    M       Oral                       100-125                         NR         Gupta (1984)
                   bubalis)

    Chicken        White Leghorn      F       Oral                       775                             93.6       Fletcher (1989)
                                                                         610-984
                                                                                                                                             

    NR, not reported

    Table 2.  Acute toxicity of malaoxon

                                                                                                                                             

    Species        Strain             Sex     Route                      LD50 and 95% CI, ±SEM,          Purity     Reference
                                                                         or range (mg/kg bw, unless      (%)
                                                                         otherwise stated) 
                                                                                                                                             

    Mouse          Swiss white        F       Oral                       215                             NR         Toia et al. (1980)

    Rat            Sprague-Dawley     M,F     Intraperitoneal            About 25                        NR         Brodeur & DuBois (1967)

    Rat            Wistar             M       Oral                       158                             NR         Dauterman & Main (1966)
                                                                         142-175
                                                                                                                                             

    NR, not reported
    

    absolute weights of the liver were increased in males at the highest
    dose and in females at the two highest doses, and periportal
    hepatocytic hypertrophy was seen at the two highest doses in animals
    of each sex. These changes were considered to be related to treatment.
    Increased relative kidney weights were observed in males at the two
    highest doses and in females at the highest dose. The NOAEL was 500
    ppm, equal to 52 mg/kg bw per day, on the basis of the increased
    weight of the livers with histopathological changes and inhibition of
    brain acetylcholinesterase activity (Daly, 1993a).

         Malathion (purity, 96.4%) was administered in the diet to groups
    of 10 male and 10 female albino Fischer (CDF:F-344/CrlBR) rats for 90
    days at concentrations of 0, 100, 500, 5000, 10 000, or 20 000 ppm,
    equal to 0, 6.6, 34, 340, 680, or 1400 mg/kg bw per day for males and
    0, 7.9, 39, 380, 780, or 1600 mg/kg bw per day for females. Body
    weight and food consumption were estimated before treatment and
    periodically during the study. Ophthalmological, haematological, and
    clinical chemical examinations, including plasma, erythrocyte, and
    brain cholinesterase activities, were undertaken before treatment and
    at termination of the study. The animals were killed at least 90 days
    after the start of the study and autopsied. Selected organs were
    examined and weighed, and all animals were examined microscopically. 

         One male at the high dose died during the study from unknown
    cause. Anogenital staining was seen in four males and six females at
    the high dose during treatment, and in animals at this dose, body
    weights and weight gain were consistently lower than in the control
    group; there was a decrease in food consumption only in week 1, in
    contrast to greater food consumption by animals at the high dose than
    by controls later in the study. Haemoglobin count and haematocrit were
    decreased in males at the high dose, while the mean corpuscular volume
    and mean cell haemoglobin were decreased in males at doses > 5000
    ppm. In females, the erythrocyte count was marginally increased at
    doses > 500 ppm, while the mean corpuscular volume was decreased at
    10 000 and 20 000 ppm, and the mean cell haemoglobin was decreased at
    doses > 5000 ppm. A number of abnormal biochemical variables were
    noted, including cholinesterase activity. Plasma cholinesterase
    activity was decreased marginally (17%) in males at 5000 ppm, while
    there was clearly significant depression at the higher doses in
    comparison with the values in concurrent controls. In female rats,
    plasma cholinesterase activity was depressed by > 20% at doses >
    5000 ppm. In the males, erythrocyte acetylcholinesterase activity was
    marginally but significantly depressed at 500 ppm (by 18% in
    comparison with concurrent controls) and markedly depressed at higher
    doses. In the females, depression of erythrocyte acetylcholinesterase
    activity by > 20% was observed at all doses. At 10 000 ppm, there was
    marginally significant depression of brain acetylcholinesterase
    activity at termination (by 13% in males and 17% in females), while at
    20 000 ppm there was biologically significant depression, by 20%, in
    males and 44% in females At 5000 ppm, there was less inhibition of
    brain acetylcholinesterase activity in animals of each sex (8.8% in
    males and 10% in females), which was, however, statistically
    significant. Significant decreases in alkaline phosphatase activity

    were seen in males at the three highest doses and in females at the
    highest dose. The activity of gamma-glutamyl transpeptidase was
    elevated in males at the highest dose and in females at the two
    highest doses. A reduction in aspartate aminotransferase activity was
    observed in females at the highest dose. 

         Differences in relative and absolute liver and kidney weights
    were seen between groups, with associated histopathological changes.
    The absolute and relative weights of the liver were increased in males
    at doses > 5000 ppm and in females at the highest dose. Periportal
    hepatocyte hypertrophy was seen in males at doses > 10 000 ppm and
    in females at doses > 5000; these changes were considered to be
    related to treatment. The absolute and relative weights of the kidney
    were increased in animals of each sex at the highest dose. At 10 000
    ppm, the absolute and relative kidney weights were increased in males
    and the relative kidney weights in females; at 5000 ppm, the relative
    kidney weights were increased in animals of each sex. Chronic
    nephropathy was more severe in males at doses > 5000 ppm than in
    those at lower doses or in controls, but there were no differences
    between groups in the prevalence of this pathological change. The
    NOAEL was 500 ppm on the basis of decreased mean corpuscular volume
    and mean corpuscular haemoglobin, increased liver weights and relative
    kidney weights, and chronic nephropathy in males at the next highest
    dose and decreased mean corpuscular haemoglobin, hepatocytic
    hypertrophy, and increased relative kidney weight in the females at
    the next highest dose. There were also marginally significant
    decreases in brain acetylcholinesterase activity at 5000 ppm. The
    finding of a marginal increase in erythrocyte count at 500 ppm in
    females is ignored. The NOAEL is equal to 34 mg/kg bw per day (Daly,
    1993b). 

     Rabbits

         Malathion (purity, 94%) was applied to the skin of groups of six
    male and six female New Zealand white rabbits for 6 h per day on five
    days per week for three weeks at doses of 50, 300, or 1000 mg/kg bw
    per day; six males and five females were sham-treated. Effects on the
    skin, organ and body weights, food consumption, clinical chemical
    parameters including cholinesterase activity, and haematological
    variables were evaluated; selected organs were examined
    pathologically. Two males, one at 50 mg/kg bw per day and one at the
    high dose, died before termination of the study,. There were no
    physical alterations or changes in body or organ weights or food
    consumption attributable to treatment, except for erythema and oedema
    in treated animals. Decreases in plasma, erythrocyte, and brain
    cholinesterase activity > 20% were seen at the highest dose in
    animals of each sex; females also showed depression of erythrocyte
    activity at 300 mg/kg bw per day. Brain acetylcholinesterase activity
    was substantially reduced in the cerebrum and cerebellum of animals of
    each sex at the highest dose. Females at 300 mg/kg bw per day had a
    19% reduction in brain acetylcholinesterase activity in comparison
    with concurrent controls, but this reduction was not statistically
    significant. The NOAEL was 300 mg/kg bw per day on the basis of

    inhibition of brain acetylcholinesterase activity at the highest dose
    (Moreno, 1989).

     Dogs

         Malathion (purity, 92.4%) was administered to groups of three
    male and three female beagles in gelatin capsules at doses of 0, 125,
    250, or 500 mg/kg bw per day for 28 days. The animals were observed
    twice daily, and haematological and clinical chemical measurements
    were made before treatment and 15 and 29 days after the start of
    treatment. Selected organs were weighed and examined  post mortem. 

         Diarrhoea was observed at all doses, and anorexia at the highest
    dose. One male at the high dose died. Weight gain was reduced at the
    highest dose and marginally so at 250 mg/kg bw per day; food
    consumption was reduced at the highest dose. At 15 days, serum albumin
    and sodium levels were decreased in dogs at the highest dose, as were
    blood urea nitrogen, aspartate aminotransferase activity, and
    creatinine. Decreased plasma and erythrocyte cholinesterase activities
    were seen at 15 days and at termination: plasma cholinesterase
    activity was decreased by > 20% in dogs at the intermediate and high
    doses at 15 days and at all doses at termination; erythrocyte
    acetylcholinesterase activity was decreased by 20% at the high dose by
    15 days and by 17% at all doses at termination. The LOAEL was 125
    mg/kg bw per day, on the basis of reduced erythrocyte
    acetylcholinesterase activity at all doses at termination of the
    study, with clinical signs (diarrhoea) at all doses. No NOAEL was
    identified (Fischer, 1988).

         Malathion (purity, 95%) was administered in capsules to groups of
    six male and six female beagles at doses of 0, 62.5, 125, or 250 mg/kg
    bw per day on seven days a week for one year. The animals were
    observed twice daily, with more detailed examinations weekly; they
    were weighed before the start of the study, at the beginning of
    treatment, weekly thereafter, and at sacrifice. Food consumption was
    measured weekly, and haematological and clinical chemical variables,
    including plasma and erythrocyte cholinesterase activity, were
    determined before treatment, at six weeks, three months, six months,
    and just before the animals were killed. Cerebellar and cerebral
    acetylcholinesterase activity was determined at termination of the
    study. Ophthalmological examination was carried before the start of
    treatment and just before sacrifice. 

         No clinical signs of toxicity were observed, nor was any
    abnormality seen on ophthalmological examination. No significant
    difference was seen in body weight or food consumption, although
    animals of each sex at the high dose showed a small decrease in mean
    weight. Clinical chemistry revealed perturbations in a number of
    variables. Plasma and erythrocyte cholinesterase activities were
    decreased by more than 20% in animals of each sex at all doses and
    times in comparison with concurrent controls. Brain
    acetylcholinesterase activity was unaffected, except for some
    diminution in cerebellar acetylcholinesterase activity at the highest

    dose (by 16% in males and 11% in females); cerebral cholinesterase
    activity was unaffected. Serum albumin, total protein, the
    albumin:globulin ratio, and calcium levels were decreased and lactate
    dehydrogenase increased in animals of each sex, generally only at the
    high dose but occasionally in those at the intermediate dose. In
    females, albumin was reduced at all doses at six weeks. Alkaline
    phosphatase activity was increased in males at the high dose but not
    in females. Other changes observed occasionally included low blood
    urea nitrogen in animals at the high dose and decreased alanine
    aminotransferase activity in those at the intermediate and high doses,
    but these did not appear to be of toxicological significance.
    Significantly lower calcium levels were found in animals at the high
    dose at six weeks and later. Haematological examination revealed
    dose-related decreases in erythrocyte and haemoglobin counts and
    haematocrit. The erythrocyte and haemoglobin counts were decreased at
    all times in males at the high dose, and the haematocrit was decreased
    in the males at the high dose at three and six months. In the females,
    erythrocyte and haemoglobin counts and haematocrit were marginally
    affected at six weeks in the group at the high dose, but at three
    months the haematocrits were decreased at the intermediate and high
    doses and haemoglobin count at the high dose. Additionally there was
    an increase in mean corpuscular volume at the high dose and in mean
    corpuscular haemoglobin at the intermediate and high doses. At six
    months, the erythrocyte and haemoglobin counts and haematocrit were
    all decreased in females at the high dose and the erythrocyte count in
    those at the intermediate dose. At termination, only a decrease in
    erythrocyte count was seen in females at the highest dose. Platelet
    counts were increased in males and females at all times and all doses
    in comparison with concurrent controls; many of these changes were
    statistically significant. Urinalysis revealed no marked changes. The
    absolute liver weights of females at the low and high doses were
    increased, and the relative liver weights were raised in males at the
    intermediate and high doses and in females at all doses. The absolute
    and relative kidney weights were raised in animals at the intermediate
    and high doses. No treatment-related pathological alteration was seen
    macroscopically or microscopically. The NOAEL was 125 mg/kg bw per day
    on the basis of body-weight depression and haematological and clinical
    chemical changes. The changes in liver weights and the reduced albumin
    in females at six weeks are discounted on the grounds that there was
    no morphological correlate and that there was no clear dose-response
    relationship (Schellenberger & Billups, 1987). 

     (c)  Long-term toxicity and carcinogenicity

         A number of long-term studies have been carried out in mice and
    rats by the US National Cancer Institute and others. Many of the
    studies were reviewed by IARC (1983) and by Rueber (1985). The working
    group convened by IARC concluded that the available data did not
    provide evidence that malathion or malaoxon is carcinogenic in humans.
    This view is in line with those of the study authors but not with
    those of Rueber (1983). More modern studies are now available and are
    summarized below, with a brief resumé of the earlier studies for the
    sake of completeness. 

     Mice

         Groups of 50 B6C3F1 mice of each sex were given doses of 0,
    8000, or 16 000 ppm malathion admixed in the diet for 80 weeks,
    equivalent to 1200 or 2400 mg/kg bw per day. The animals were killed
    14-15 weeks after discountinuation of the malathion-containing diets.
    Throughout the study, the mean body weights of animals of each sex
    were lower than those of controls; poor food consumption,
    hyperexcitability, and abdominal distention were also noted in the
    second year; tremors were seen in a few female mice. Malathion was
    reported not to be carcinogenic (US National Cancer Institute, 1978);
    however, the slides were re-examined by Rueber (1985), who concluded
    that malathion had increased the incidence of neoplasms of the liver
    in male mice. 

         Malathion (purity, 96.4%) was administered in the diet to groups
    of 65 B6C3F1 BR mice of each sex for 18 months at concentrations of 0,
    100, 800, 8000, or 16 000 ppm (equal to 0, 17, 140, 1500, or 3000
    mg/kg bw per day for males and 0, 21, 170, 1700, and 3500 mg/kg bw per
    day for females). Animals were observed twice daily and examined in
    detail weekly. Body weights were determined weekly until week 14,
    fortnightly to week 26, and monthly thereafter. Plasma, erythrocyte,
    and brain cholinesterase activity was determined 10 animals of each
    sex from each group killed at 12 months and at termination; only
    erythrocyte enzyme activity was determined in 10 mice of each sex per
    group at week 36, and these mice were retained until terminal
    sacrifice of the survivors at 18 months. The mice were examined 
     post mortem, and selected organs were processed and examined
    histologically. 

         There was no treatment-related effect on mortality, but body
    weights and food consumption were reduced in animals of each sex at
    8000 and 16 000 ppm. Plasma cholinesterase activity was reduced by
    > 20% in comparison with concurrent controls at 12 and 18 months in
    males at 800 ppm; similar results were seen in females, except that
    the reduction was 18% in those at 800 ppm by 12 months. Erythrocyte
    acetylcholinesterase activity was decreased by > 20% in animals of
    each sex at doses > 800 ppm at 9, 12, and 18 months, while brain
    acetylcholinesterase activity was decreased in males at the highest
    dose at 12 and 18 months and in those at 8000 ppm at 18 months. In
    females, brain acetylcholinesterase activity was not decreased at 8000
    ppm at 12 months but was decreased at 18 months; females at 16 000 ppm
    showed a 20% decrease in brain acetylcholinesterase activity at
    12 months and a 43% decrease at 18 months. The absolute and relative
    liver weights were increased in males at the two highest doses, and
    the relative liver weight was increased in females at the highest
    dose. Other changes in organ weights included increased relative
    kidney weights in certain groups. 

         Macroscopically, an increased incidence of liver nodules was seen
    at the two highest doses; microscopically, effects were seen on the
    liver, kidney, adrenal cortex, and bone. Liver hepatocellular
    hypertrophy was observed in all animals at the two highest doses at

    termination, and milder hypertrophy was seen in the animals killed at
    12 months. The incidences of liver tumours in animals that survived to
    termination are given in Table 3. There was a significant trend in the
    incidence of adenomas in animals of each sex, and the incidence was
    significantly raised by comparison with controls at the two highest
    doses; the incidences in historical controls at the same laboratory
    were 14-22% in males and 0-11% in females. There was no significant
    trend for hepatocellular carcinoma, but the incidence was
    significantly raised in the males at 100 and 8000 ppm. 

         Proximal tubular vacuolation seen at lower doses in the kidneys
    was absent in all males at the highest dose and most of those at 8000
    ppm. Female mice at 8000 and 16 000 ppm had an increased incidencse of
    renal cortical mineralization. A treatment-related decrease in fibrous
    osteodystrophy of the sternum observed in females at the highest dose
    is of unknown significance. A treatment-related, early disappearance
    of the X zone of the adrenal cortex was observed in females at 8000
    and 16 000 ppm at 12 months. The overall NOAEL was 800 ppm, equal to
    140 mg/kg bw per day, on the basis of inhibition of brain
    acetylcholinesterase activity and an increased incidence of liver
    adenomas in animals of each sex at the next highest dose (Slauter,
    1994).

     Rats

     Malathion

         Three studies were carried out by Hazleton Laboratories (Hazleton
    & Holland, 1953). In the first, groups of 20 male Colworth Farm rats
    were given technical-grade malathion (purity, 65%) in the diet at
    doses of 0, 100, 1000, or 5000 ppm, equivalent to 5, 50, and 250 mg/kg
    bw per day, for 109 weeks. Body weight and food consumption were
    decreased in those at the highest dose. Depressed cholinesterase
    activity was seen in rats at 5000 ppm and to a lesser extent in those
    at 1000 ppm. The study was not adequate for conclusions to be drawn
    about carcinogenicity. In the second study, with the same doses,
    similar criticisms can be made, except that the purity of the
    malathion was > 90%. A third study was carried out with male and
    female Colworth Farm rats which received doses of 0, 500, 1000, 5000,
    or 20 000 ppm of malathion (purity, 99%). The highest dose was lethal
    to the male rats; the size of the study precluded conclusions about
    carcinogenicity. 

         Groups of 50 male and 50 female Osborne-Mendel rats were given
    technical-grade malathion (purity, 95%) in the diet at concentrations
    of 4700 or 8150 ppm (equivalent to 240 and 410 mg/kg bw per day) for
    80 weeks. A pooled control group consisted of 15 matched controls of
    each sex and 40 untreated male and female rats from bioassays of other
    chemicals. The rats were killed after 109 weeks. The body weights of
    female rats receiving malathion were lower than those of controls, and
    the survival times of those at the higher dose were decreased.
    Malathion was reported not to be carcinogenic (US National Cancer
    Institute, 1978). The slides were re-evaluated by Rueber (1985), who


        Table 3. Incidences of hepatocellular tumours (%) in mice at terminal sacrifice after treatment with malathion

                                                                                                                    

    Tumour         Dose (ppm)
                                                                                                                    
                   Males                                             Females
                                                                                                                    
                   0         100       800       8000      16 000    0         100       800       8000      16 000
                                                                                                                    

    Adenoma        2         11.8      4.2       24.1      98.0      0         1.9       0         17.9      82.4

    Carcinoma      0         11.8      4.2       11.1      2.0       1.8       0         3.8       1.9       3.9
                                                                                                                    
    

    found that the incidence of benign and malignant neoplasms at all
    sites analysed together was increased in treated rats; in particular,
    the incidence of carcinomas of the endocrine organs was increased, and
    malignant neoplasms of the brain were observed in seven treated rats.
    Rueber concluded that malathion was carcinogenic in male and female
    Osborne-Mendel rats. In a re-evaluation of the slides commissioned by
    the US National Toxicology Program (Huff et al., 1985), the original
    interpretation that malathion is not carcinogenic was confirmed.

         In a second study by the US National Cancer Institute (1979a),
    malathion (purity, 95%) was fed in the diet to groups of 50 male and
    50 female Fischer 344 rats at doses of 0, 2000, or 4000 ppm
    (equivalent to 100 or 200 mg/kg bw per day; only 49 males at the
    higher dose) for 103 weeks. The authors concluded that malathion was
    not carcinogenic. When Rueber (1985) re-evaluated the slides, he found
    that the incidence of benign and malignant neoplasms analysed together
    was significantly increased, particularly in males. He concluded that
    malathion was carcinogenic in Fischer 344 rats. A re-evaluation of the
    slides commissioned by the US National Toxicology Program (Huff et
    al., 1985) confirmed that malathion was not carcinogenic.

         Malathion (purity, 92.1%) was given in the diet to groups of 50
    male and 50 female Sprague-Dawley rats at concentrations of 0, 100,
    1000, or 5000 ppm, equivalent to 5, 50, or 250 mg/kg bw per day. The
    animals were observed daily throughout the study, and body weights and
    food consumption were recorded at the end of weeks 1, 13, 24, 53, 79,
    and 103. Blood samples for haematological examination and
    determination of cholinesterase activity and urine samples for
    urinalysis were collected from five rats of each sex per group in
    weeks 12, 26, and 53; blood and urine were also collected at week 104,
    and alanine and aspartate aminotransferase activities, urea nitrogen,
    and glucose were determined additionally in blood. Brain
    acetylcholinesterase activity was not determined. Animals that died,
    were killed  in extremis, or killed at termination were examined
     post mortem. 

         No significant difference in food consumption or survival was
    seen, and no significant intergroup differences were seen on
    haematological or biochemical examination, except in cholinesterase
    activity. During the first year of the study, the body weights of
    animals of each sex at the highest dose were reduced, while in the
    second year the body weights of those at 1000 and 5000 ppm were
    depressed. Moreover, erythrocyte acetylcholinesterase activity was
    reduced by > 20% in comparison with the controls in rats at the
    intermediate and high doses at 3, 6, 12, and 24 months; plasma
    cholinesterase activity was less affected, although there was a
    depression of > 20% in the females at the high dose at 12 and 24
    months. Absolute and relative liver weights were increased in male
    rats at the high dose and relative kidney weights in males at the two
    highest doses. Absolute brain weights were decreased in females at the
    two highest doses and relative kidney weights in those at the high
    dose. 

         Although foci of cellular alteration were recorded twice in the
    livers of males at the highest doses and once in females at the
    intermediate and high doses, this difference was not statistically
    significant. A significant difference in sinusoidal dilatation was
    found between the controls (2%) and males at the high dose (16%).
    Extramedullary splenic haematopoiesis was seen more often in males at
    the high dose than in controls. There was no evidence of carcinogenic
    potential. The NOAEL was 100 ppm, equivalent to 5 mg/kg bw per day, on
    the basis of reduced erythrocyte acetylcholinesterase activity and
    body weight at the next highest dose (Rucci et al., 1980). After an
    audit by the US Environmental Protection Agency (1987; Cyanamid,
    1990), the Agency requested a re-evaluation of the slides. Seely
    (1991) found only two treatment-related lesions: periportal
    hepatocellular hypertrophy and cystic hepatocellular degeneration,
    both only in male rats at the highest dose. There was no evidence of
    differences in tumour incidence. The NOAEL for effects on the liver
    was thus 1000 ppm (equivalent to 50 mg/kg bw per day). This
    re-evaluation does not alter the overall NOAEL of 5 mg/kg bw per day
    (see above).

         Malathion (purity, 96.4%) was administered in the diet of groups
    of 90 male and female Fischer 344 (CDF:F-344/CrlBR) rats at
    concentrations of 0, 100/50, 500, 6000, or 12 000 ppm for two years;
    the lowest dose was reduced from 100 to 50 ppm at week 18 because of
    inhibition of erythrocyte acetylcholinesterase activity, resulting in
    mean intakes over the entire study of 0, 4, 29, 360, and 740 mg/kg bw
    per day for males and 0, 5, 35, 420, and 870 mg/kg bw per day for
    females. Groups of 10 animals of each sex per group were killed at
    three and six months, 15 of each sex per group at 12 months, and the
    remainder at two years. Physical condition, ophthalmoscopic
    parameters, body weight, and food consumption were determined before
    treatment and at selected intervals, while electroretinography,
    haematology, and clinical chemistry (including determination of
    cholinesterase activity) were performed at selected intervals and on
    selected animals. Selected organs from animals killed at 12 and 24
    months were weighed, and the animals were examined macroscopically.
    Tissues from those at the high dose and from controls, and certain
    organs from animals at the low dose were examined histopathologically.

         Malathion reduced the survival of males at 6000 and 12 000 ppm,
    early deaths being observed from the 14th month in males at the
    highest dose and from about the 20th month in those at the next lowest
    dose. Survival of females at the high dose was impaired towards the
    end of the study. Nephropathy and mononuclear-cell leukaemia were the
    main causes of death, although the frequency of neither was
    treatment-related. Anogenital staining was seen in females at the
    highest dose. Decrements in body weight and weight gain were seen in
    animals of each sex throughout the study at the two highest doses,
    although mean food consumption was greater in these animals than in
    the controls, throughout the study in the case of the males and in the
    second year of the study in the case of the females. Decreases in mean
    haemoglobin concentration, haematocrit, mean corpuscular volume, and
    mean cell haemoglobin were seen in animals of each sex at the two

    highest doses at 6, 12, and 18 months, although all parameters were
    not affected at all the time intervals and there was a tendency for
    improvement during the study. The mean cell haemoglobin concentration
    was decreased in males at the two highest doses only at 12 months,
    accompanied by an increase in platelet count. 

         At 3, 6, 12, and 24 months, animals of each sex showed reductions
    in plasma, erythrocyte, and brain cholinesterase activity,
    predominantly at the two highest doses. Thus, animals of each sex at
    the highest dose had decreased plasma cholinesterase activity at all
    times. In males at 6000 ppm, decreases in activity > 20% were seen at
    three and six months and at termination, while there was a marginal
    decrease at 12 months (83% of control value). Males at 500 ppm had a
    significant decrease in activity only at termination, when the
    activity was 71% of that of concurrent controls. In the females,
    plasma cholinesterase activity was consistently reduced by at the two
    highest doses; the activity was little affected at 500 ppm, except at
    termination when there was a marginally significant decrease of 18%.
    There were consistent reductions in erythrocyte acetylcholinesterase
    activity at the two highest doses in males and a marginally
    significant reduction at 500 ppm at termination only, when the
    activity was 83% that of concurrent controls. Erythrocyte
    acetylcholinesterase activity was similarly reduced in females at 6000
    and 12 000 ppm. Although reductions > 20% were seen in females at 500
    ppm at three months and at termination and a marginal reduction at 12
    months (86% of control value), no reduction was seen at six months.
    Erythrocyte acetylcholinesterase activity was also reduced in females
    at the lowest dose at three months (75% of control value), so that on
    day 113 the lowest dose was reduced from 100 ppm to 50 ppm. Six weeks
    later, erythrocyte acetylcholinesterase activity was evaluated in 10
    controls and 10 at 50 ppm and found to be comparable. Thereafter, the
    activity in animals at 50 ppm was unremarkable. Brain
    acetylcholinesterase activity was reduced by > 20% in males at 6000
    ppm at termination. Decreases seen at the highest dose were 84% of the
    control value at three months, 81% at six months, and 85% at 12
    months; no determination was carried out at termination because there
    were no survivors. At 6000 ppm, the activity was decreased to 88% of
    the control value at three months, 88% at six months, and 89% at 12
    months. In females at 12 000 ppm, the activity of brain
    acetylcholinesterase was substantially reduced in comparison with that
    of concurrent controls. Smaller decreases were seen at 6000 ppm at
    three months (15%), six months (17%), 12 months (12%), and termination
    (18%). No significant inhibition was seen at lower doses. 

         Alkaline phosphatase activity was reduced in comparison with
    concurrent controls in animals of each sex at the two highest doses at
    6 and 12 months and at the highest dose at 18 months. Aspartate
    aminotransferase activity was reduced in females at doses > 500 ppm
    at 12 months and at the highest dose at 18 months. Alanine
    aminotransferase activity was also decreased in females at the three
    highest doses at 12 months. gamma-Glutamyl transpeptidase activity was
    increased consistently in males at the two highest doses from 12
    months and at most intervals in females. Cholesterol content was

    increased in animals of each sex at the two highest doses at 6, 12,
    18, and 24 months. Increases in mean and relative liver and kidney
    weights were observed in animals of each sex at the two highest doses
    at the interim sacrifice, in females at 6000 and 12 000 ppm at
    terminal sacrifice, and in males at 6000 ppm at terminal sacrifice.
    Males also had decreased relative kidney weights at 500 ppm. Relative
    spleen weight was increased in males at the two highest doses at
    interim sacrifice, and absolute spleen weight was reduced in males at
    6000 ppm and in females at 12 000 ppm at terminal sacrifice. Relative
    and absolute thyroid and parathyroid weights were elevated in males at
    the two highest doses at interim sacrifice, in males at 6000 ppm at
    termination, and in females at 6000 and 12 000 ppm at termination. 

         Microscopic findings of significance were largely confined to
    nasoturbinal tissues, kidney, and liver. Degeneration and hyperplasia
    of the olfactory epithelium were seen in animals of each sex at the
    two highest doses. The hyperplasia was focal, with thickening of the
    epithelium and proliferation of basal cells, forming clusters in the
    lamina propria. While focal degeneration was also observed in a few
    controls and rats at lower doses, the hyperplasia was confined to
    those at the two highest doses. In several rats, the epithelium was
    replaced by ciliated and non-ciliated columnar epithelium. Subacute
    and chronic inflammation and dilated and hyperplastic mucosal glands
    were seen in some animals; subacute and chronic inflammation and
    hyperplasia of the respiratory epithelium of the nasopharynx and
    dilated mucosal glands were also seen. Like the other changes in nasal
    tissues, inflammatory cells and cell debris were seen most frequently
    at the two highest doses. Thus, the NOAEL for this effect was 500 ppm.
    The incidence and severity of nephropathy was greater in rats at 6000
    and 12 000 ppm than in controls. 

         A nasal turbinate adenoma was seen in one male at 6000 ppm and a
    carcinoma in one male at 12 000 ppm; although the numbers observed
    were small, this is a rare tumour in Fischer rats. Hepatocellular
    adenomas and carcinomas were seen in some animals. In the female rats,
    the prevalence of adenomas and cacinomas combined was increased at the
    highest dose and that of adenomas alone at 6000 ppm (see Table 4).
    Testicular interstitial-cell tumours were seen in virtually all male
    rats that survived to termination. The overall NOAEL was 500 ppm,
    equal to 29 mg/kg bw per day, on the basis of decreased survival and
    body-weight gain, increased food consumption, changes in
    haematological parameters, decreased brain acetylcholinesterase
    activity, increased g-glutamyl transpeptidase activity, increased
    liver, kidney, thyroid, and parathyroid weights, and degeneration and
    hyperplasia of the olfactory epithelium at the next highest dose.
    Although an increased incidence of liver tumours was seen in females,
    malathion was not considered to be carcinogenic in view of the small
    numbers of such tumours observed (Daly, 1996a).


        Table 4.  Prevalences of hepatocelular adenomas and carcinomas in rats at termination after treatment with malathion

                                                                                                                            
                        Dose (ppm)
                                                                                                                            
                        Males                                             Females
                                                                                                                            
                        0         100/50    500       6000      12 000    0         100/50    500       6000      12 000
                                                                                                                            

    No. of animals      37        41        29        14        0         38        41        41        34        20

    Tumour
      Adenoma           2         2         3         1         0         0         0         1         3         3
      Carcinoma         1         1         0         1         0         0         1         1         0         1
                                                                                                                            
    

     Malaoxon 

         Malaoxon (purity, > 95%) was fed to groups of 50 Fischer 344
    rats of each sex in the diet at concentrations of 0, 500, or 1000 ppm
    for 103 weeks. The authors concluded that malaoxon was not
    carcinogenic in rats (US National Cancer Institute, 1979b). The slides
    were re-examined by Rueber (1985), who concluded that the incidence of
    benign and malignant neoplasms at all sites was increased in the
    treated animals. The neoplasms in question were in endocrine organs,
    including the pituitary, adrenal, and thyroid glands; the incidences
    of hyperplasia, adenomas, and carcinomas of C cells of the thyroid
    were increased. In a re-evaluation of the slides commissioned by the
    US National Toxicology Program (Huff et al., 1985), the original
    conclusion that malaoxon is not carcinogenic was largely confirmed,
    but there was stated to be equivocal evidence that malaoxon is
    carcinogenic in that there was an increased incidence of C-cell
    neoplasms of the thyroid. 

         Groups of 85 Fischer 344 (CDF:F-344/CrlBR) rats of each sex were
    exposed to malaoxon (purity, 96.4%) admixed in the diet at
    concentrations of 0, 20, 1000, or 2000 ppm (equal to 1, 57, or
    110 mg/kg bw per day in males and 1, 68, or 140 mg/kg bw per day in
    females); 55 animals were retained for 24 months, while 10 of each sex
    per group were killed at 3, 6, and 12 months. Cholinesterase activity
    was estimated in all animals. Clinical chemical and haematological
    parameters were determined in all animals killed at 6 and 12 months
    and in 10 animals of each sex per group of animals that were retained
    at 18 months and termination. Physical observations, ophthalmoscopy,
    and measurements of body weight and food consumption were carried out
    before treatment and at selected intervals during the study. The
    surviving rats were sacrificed at 24 months. The rats were examined
     post mortem, and selected organs were weighed. Histopathological
    examinations were perfomed on controls and those at the high dose at
    12 and 24 months and on rats that died or were killed  in extremis 
    during the study. Selected tissues from animals at the intermediate
    and low doses were also examined. 

         Survival was curtailed in female rats at 1000 and 2000 ppm and in
    males at 2000 ppm. The most common causes of death were pneumonitis
    and mononuclear leukaemia; the occurrence of the former appeared to be
    dose-related. Anogenital staining was seen in females at the highest
    dose throughout the study and in males in the latter part of the
    study. Treatment-related decreases in body weight and weight gain were
    seen at the highest dose. Food consumption was decreased in males at
    1000 and 2000 ppm. Plasma, erythrocyte, and brain cholinesterase
    activity was affected by malathion. Plasma cholinesterase activity was
    reduced by > 20% at all times in animals of each sex at the two
    highest doses. Erythrocyte acetylcholinesterase activity was reduced
    by > 20% in the same groups and in males at the lowest dose at six
    months; the reductions at other times in animals of each sex at this
    dose were 10-20%. Brain acetylcholinesterase activity was reduced by
    18-11% in comparison with concurrent controls in males at the highest
    dose and more clearly reduced in females at earlier times. There were

    substantial reductions in brain acetylcholinesterase activity in
    animals of each sex at the highest dose at termination of the study.
    At the intermediate dose, there was a 30% decrease in brain
    acetylcholinesterase activity in males at termination. 

         No abnormality was seen on ophthalmoscopic examination. Although
    there were sporadic differences in clinical chemical measurements
    between groups, none appeared to be treatment-related. The absolute
    and relative liver and kidney weights were increased in males at 2000
    ppm at 12 months, and the relative and absolute adrenal weights were
    increased in males at this dose at two years. The absolute and
    relative spleen weights of females at 2000 ppm were decreased. The
    incidence of emaciation: was increased in males at 2000 ppm and in
    females at 1000 and 2000 ppm. Inflammatory changes in the nasal
    turbinates, lungs, and tympanic spaces, which may have been secondary
    to increased disposition of food particles, were present in males at
    the highest dose and females at the two highest doses. Thus, foreign
    material such as food was found in the nasal lumen with inflammatory
    cells and cell debris. The nasal mucosa also showed chronic
    inflammatory changes and hyperplasia and hypertrophy of goblet cells.
    In a small number of rats, squamous metaplasia was observed.
    Degeneration of the olfactory epithelium was accompanied by focal
    replacement by ciliated and non-ciliated columnar epithelium.
    Mineralization of the stomach was seen in males at the two highest
    doses and females at the highest dose. No treatment-related neoplasia
    was observed. Interstitial tumours of the testis were present in
    > 75% of the animals at all doses and were not considered to be
    related to treatment. The NOAEL was 20 ppm, equal to 1 mg/kg bw per
    day, on the basis of decreased food consumption and brain
    acetylcholinesterase activity at termination in males and emaciation
    at termination and inflammatory changes in the nasal turbinates in
    females at the next highest dose (Daly, 1996b).

     (d)  Genotoxicity

         The results of tests for the genotoxicity of malathion and
    malaoxon are shown in Table 5. Four impurities in malathion,
    isomalathion,  O,O,S-trimethyl phosphorothioate,  O,S,S-trimethyl
    phosphorodithioate, and  O,O,O-trimethyl phosphorothioate of > 99%
    purity were tested for their potential to induce reverse mutation in
     S. typhimurium TA97, TA98, and TA100 at doses of 10-1000 µg/plate.
    Negative results were obtained, with and without metabolic activation
    and with and without preincubation (Imamura & Talcott, 1985).

     (e)  Reproductive toxicity

     (i)  Multigeneration reproductive toxicity

         In a small study in Wistar rats given malathion in the diet at
    about 240 mg/kg bw, a higher incidence of ring-tail disease was seen
    in treated than in control rats (Kalow & Marton, 1961).


        Table 5. Results of tests for the genotoxicity of malathion and malaoxon

                                                                                                                                 

    End-point               Test system               Concentration             Purity    Results         Reference
                                                                                (%)
                                                                                                                                 

    Malathion
    In vitro
    Reverse mutation        S. typhimurium            NR                        NR        Negativea       McCann et al. (1975)
                            TA98, TA100,
                            TA1535, TA1537

    Reverse mutation        S. typhimurium            100-5000 µg/plate         95.2      Negativea       Traul (1987)
                            TA98, TA100,
                            TA1535, TA1537,
                            TA1538

    Reverse mutation        S. typhimurium            5-300 µg/plate            NR        Positive        Shiau et al. (1980)
                            TA98, TA100,                                                  (TA 1535
                            TA1535, TA1536,                                               without S9)
                            TA1537, TA1538

    Reverse mutation        S. typhimurium            33-165 µg/plate           NR        Negativeb       Pednekar et al. (1987)
                            TA97a, TA98, TA100

    Reverse mutation        S. typhimurium            NR                        NR        Negative        Byeon et al. (1976)c
                            TA98, TA100,
                            TA1535, TA1538

    Reverse mutation        S. typhimurium            80 and 400 ppm/plate      90-95     Negativea       Wong et al. (1989)
                            TA98, TA102,
                            TA1535, TA1537

    Reverse mutation        S. typhimurium            < 5000 µg/plate           NR        Negativea       Moriya et al. (1983)
                            TA98, TA100,
                            TA1535, TA1537,
                            TA1538

    Table 5. (continued)

                                                                                                                                 

    End-point               Test system               Concentration             Purity    Results         Reference
                                                                                (%)
                                                                                                                                 

    Reverse mutation        S. typhimurium            < 10 mg/plate             NR        Negativea       Waters et al. (1982)
                            TA98, TA100,
                            TA1535, TA1537,
                            TA1538

    Reverse mutation        S. typhimurium            NR (preincubation)        NR        Positive        Ishidate et al. (1981)
                            TA98, TA100,                                                  (TA 100 with
                            TA1537                                                        S9)

    Reverse mutation        Escherischia coli         NR                        NR        Negativea       Nagy et al. (1975)

    Reverse mutation        Escherischia coli         100-5000 µg/plate         95.2      Negativea       Traul ( t 987)

    Reverse mutation        Escherischia coli         < 5000 µg/plate           NR        Negativea       Moriya et al. (1983)

    Reverse mutation        Escherischia coli         < 10 mg/plate             NR        Negativea       Waters et al. (1982)

    Forward mutation        Escherischia coli         2 × 20 mol/L              NR        Negative        Mohn (1973)

    Forward mutation        Schizosaccharomyces       NR                        99        Negative        Degraeve et al. (1980)
                            pombe

    Forward mutation        Schizosaccharomyces       30-182 mmol/L             NR        Negativea       Gilot-Delhalle et al.
                            pombe                                                                         (1983)

    DNA damage              Bacillus subtilis         5-300 µg/plate            NR        Positive        Shiau et al. (1980)
                            rec and exc

    DNA damage              Bacillus subtilis rec     200 µg/plate              NR        Negative        Shirasu et al. (1976)

    DNA damage              Bacillus subtilis rep     NR                        NR        Negative        Waters et al. (1982)

    Table 5. (continued)

                                                                                                                                 

    End-point               Test system               Concentration             Purity    Results         Reference
                                                                                (%)
                                                                                                                                 

    DNA damage              Bacillus subtilis rew     NR                        NR        Negative        Waters et al. (1982)

    Primary DNA             Saccharomyces             NR                        NR        Negative        Waters et al. (1982)
      damage                cerevisiae

    Unscheduled             Primary rat               0.01-0.16 µl/ml           94        Negative        Pant (1989)
      DNA synthesis         hepatocytes

    Unscheduled             Human lung                NR                        NR        Negativea       Waters et al. (1982)
      DNA synthesis         fibroblasts

    Chromosomal             Chinese hamster           NR                        NR        Positivea       Ishidate et al. (1981)
      aberration            lung fibroblasts

    Chromosomal             Cultured human            0.02-20 µg/ml             NR        Positive        Balaji & Sasikali (1993)
      aberrations           peripheral leukocytes

    Sister chromatid        Cultured human            0.02-20 µg/ml             NR        Positive        Balaji & Sasikali (1993)
      exchange              peripheral leukocytes

    Chromosomal             Cultured human            33-660 µg/ml              NR        Positivea       Garry et al. (1990)
     aberrations            peripheral leukocytes

    Sister chromatid        Cultured human            33-660 µg/ml              NR        Positivea       Garry et al. (1990)
     exchange               peripheral leukocytes

    Sister chromatid        Human fetal fibroblasts   2.5-40 µg/ml              99        Positive        Nicholas et al. (1979)
     exchange

    Table 5. (continued)

                                                                                                                                 

    End-point               Test system               Concentration             Purity    Results         Reference
                                                                                (%)
                                                                                                                                 

    Sister chromatid        Chinese hamster V79       10-80 µg/ml               94        Positive        Chen et al. ( 1981)
     exchange/cell          cells                                                         (high dose)
     cycle delay

    Sister chromatid        Chinese hamster ovary     0.03-1 mmol/L             99        Positive        Nishio & Yueki (1981)
     exchange               cells

    In vivo
    Sex-linked recessive    Drosophila melanogaster   Feeding: adult, 50 ppm;   50%       Negative        Velazquez et al. (1987)
      lethal mutation                                 larva, 100 ppm                      ECd
                                                      Injection: adult, 10 and
                                                      25 ppm

    Sex-linked recessive    Drosophila melanogaster   NR                        NR        Negative        Waters et at. (1982)
      lethal mutation

    Sex chromosome          Drosophila melanogaster   Feeding: 0-10 ppm         50%       Negative        Velazquez et al. (1987)
      loss                  adult                     Injection: 0 and 5 ppm    ECd

    Non-disjunction         Drosophila melanogaster   Feeding: 0-20 ppm Ecd     50%       Negative        Velazquez et al. (1987)

    Dominant lethal         Mouse                     NR                        NR        Negative        Degraeve et al. (1980)
      mutation

    Dominant lethal         Mouse                     'Maximum lethal dose'     NR        Negative        Waters et al. (1982)
      mutation

    Chromosomal             Rat bone marrow           0.5-2.0 g/kg              94        Negative        Gudi (1990)
      aberration            (Sprague-Dawley)

    Chromosomal             Syrian hamster bone       0.24-1.2 g/kg             30e,f      Positive        Dzwonkowska &
      aberration            marrow                                                                        Hubner (1986)

    Table 5. (continued)

                                                                                                                                 

    End-point               Test system               Concentration             Purity    Results         Reference
                                                                                (%)
                                                                                                                                 

    Chromosomal             CFW mouse spermatocytes   0.45 mg/day for           30f       Positive        Bulsiewicz et al. (1976)
      aberration                                      50 or 100 days

    Chromosomal             Mouse bone marrow and     500-2000 mg/kg bw         NR        Positive        Salvadori et al. (1988)
      aberration            primary spermatocytes     single dose or 5 daily
                                                      doses dermally

    Malaoxon

    In vitro
    Reverse mutation        S. typhimurium            100-10 000 µg/plate       94.4      Negativea       Zeiger et al. (1988)
                            TA97, TA98, TA100,
                            TA1535, TA1537

    Cell mutation           Mouse lymphoma            12.5-300 nl/ml            NR        Positive        Myhr & Caspary (1991)
     tk locus               L5178Y cells                                                  without S9;
                                                                                          equivocal with
                                                                                          S9

    Sister chromatid        Chinese hamster ovary     0.03-1 mmol/L             96        Positive        Nishio & Yueki (1981)
      exchange              cells

    Chromosomal             Chinese hamster ovary     > 5 mg/ml                 94.4      Negative        Ivett et al. (1989)
      aberration            cells

    Sister chromatid        Chinese hamster ovary     > 5 mg/ml                 94.4      Positivea       Ivett et al. (1989)
     exchange               cells

    In vivo
    Sex-linked recessive    Drosophila melanogaster   Feeding: 5 ppm            94.4      Positive        Foureman et al. (1994)
      lethal mutation                                 Injection: 2 ppm                    feeding;
                                                                                          negative,
                                                                                          injection

    Table 5. (continued)


    NR, not reported; S9, 9000 × g supernatant of rodent liver
    a With and without metabolic activation
    b With and without metabolic activation with S9 and caecal microbial extract
    c In Korean; not fully evaluated
    d 50% emulsifiable concentrate
    e 30% commercial preparation from Organika-Azot, Poland
    f Sadofos-30 (approximately 30% solution)
    

         In a two-generation study of reproductive toxicity, groups of 25
    male and 25 female CD:Sprague-Dawley-derived rats were fed diets
    containing malathion (purity, 94%) at concentrations of 0, 550, 1700,
    5000, or 7500 ppm, equal to 0, 43, 130, 390, or 600 mg/kg bw per day
    in the F0 males and 0, 50, 150, 440, and 660 mg/kg bw per day in the
    F0 females. The equivalent intakes for the F1 generation were: 43,
    130, 390, or 630 mg/kg bw per day for males and 51, 150, 460, and 750
    mg/kg bw per day for females. Each parent generation was mated to
    produce two litters, and offspring were selected randomly from the
    second (F1b) litter to be the parents of the next generation.
    Offspring that were not selected, the offspring of the first litters
    (F1a and F2a), and the F2b offspring were examined grossly and
    discarded. One pup of each sex per F1b and F2b litter was selected
    randomly, killed, and examined  post mortem; abnormal tissues were
    saved. The F0 and F1 adults were killed and examined  post mortem, 
    and the reproductive organs and abnormal tissues were saved. Tissues
    from the controls and animals at the high dose were examined
    histologically. 

         Treatment had no effect on clinical signs, growth before mating,
    food consumption, maternal weight gain during gestation, reproductive
    performance, fertility indices, gestation length, or parturition in
    the F0 and F1 parental generations. Pup sex ratio and survival were
    also unaffected. Pup weight was reduced at day 21 in the F1a litters
    at 5000 and 7500 ppm and in the F1b litters at 7500 ppm. Mean pup
    weights in the F2a litters were comparable in all groups, except in
    those at the high dose on day 21, which were decreased. Pup weights
    were reduced at days 4, 7, 14, and 21 in the F2b litters at 5000 ppm
    but not at 7500, except on day 21. At the highest dose, mean pup
    weight at day 21 was lower than that of concurrent controls. Similar
    effects were not seen at lower doses. Examination  post mortem showed
    no treatment-related effects. The NOAEL for reproductive toxicity was
    7500 ppm, equal to 600 mg/kg bw per day, while that for developmental
    toxicity was 1700 ppm, equal to 130 mg/kg bw per day (Schroeder,
    1990).

         In a study reported briefly, malathion (purity unspecified) was
    administered to 16 male JIPMER albino rats for 12 weeks at a dose of
    45 mg/kg bw per day by gavage. There were 12 appropriate controls. The
    histological changes observed included interstitial oedema,
    congestion, desquamation of cells lining the seminiferous tubules,
    reduced numbers of spermatogonia, and absence of Leydig cells
    (Balasubramanian  et al., 1987). 

     (ii)  Developmental toxicity

         Female Sherman-strain rats were pair-mated with healthy adult
    male rats of about the same age. On day 11 after insemination, they
    were given a single intraperitoneal injection of malathion at a dose
    of 700 or 900 mg/kg bw. On day 20 of gestation, the fetuses were
    removed. The offspring and placentae were weighed, the numbers of
    resorptions and dead animals were recorded, and half of the offspring

    were examined in detail. The higher dose of malathion affected the
    body weight of the dams but had no effect on the weight of the fetuses
    and did not induce malformations (Kimbrough & Gaines, 1968).

         Technical-grade malathion (purity unspecified) was administered
    by gavage to groups of 20 female Wistar rats at doses of 0, 50, 100,
    200, or 300 mg/kg bw on days 6-15 of gestation. Neither maternal nor
    fetal toxicity was observed at the highest dose used (Khera et al.,
    1978).

         After a dose-ranging study, groups of female Crl:CD:(SD)BR rats
    were given malathion (purity, 94%) by gavage on days 6-15 of gestation
    at doses of 0, 200, 400, or 800 mg/kg bw per day in corn oil; the
    groups consisted of 24 rats at the lowest dose and 25 at the other
    doses. The animals were observed daily for clinical signs, body-weight
    gain, and food consumption. After 20 days, the rats were killed and
    examined for pregnancy, implantations, resorptions, live and dead
    fetuses, and number of corpora lutea; the uterus was weighed, and
    fetuses were examined for malformations. Cholinesterase activity was
    not measured in this study. Malathion had no effect on survival, the
    only early death occurring in the control group. Five rats at the
    highest dose had urine staining of abdominal fur and decreased mean
    weight gain and food consumption during treatment; after treatment,
    the weight gain of animals at the high dose was increased in
    comparison with the controls. No effect was seen on pregnancy rate or
    numbers of corpora lutea, implantations, resorptions, or fetuses per
    litter, fetal body weight, or sex ratio of fetuses. No fetal
    abnormality attributable to treatment was observed. The NOAEL was 400
    mg/kg bw per day on the basis of maternal toxicity at the highest
    dose. The NOAEL for fetal toxicity was 800 mg/kg bw per day (Lochry,
    1989).

         Malathion (70% with 30% calcium carbonate) was administered at a
    dose of 100 mg/kg bw per day on days 7-12 of gestation to seven mated
    New Zealand white rabbits. Five mated rabbits received the vehicle
    alone. No difference between the treated and control groups was seen
    in respect of resorptions, fetal size, or external or visceral
    abnormalities. The NOAEL for effects on the fetus was thus 100 mg/kg
    bw per day. It is unclear from the paper whether any significant
    maternal toxicity was observed (Machin & McBride, 1989). 

         After a range-finding study, malathion (purity, 92.4%) was
    administered at doses of 25, 50, or 100 mg/kg bw per day by gavage in
    corn oil to groups of 20 mated female New Zealand white rabbits on
    days 6-18 of gestation; controls received the vehicle alone. The
    rabbits were examined daily for mortality and for physical and
    behavioural abnormalities. Body-weight gain was calculated for days
    0-6, 6-12, 6-18, 18-29, and 0-29 days after the start of the study and
    on days 6, 12, 18, and 29. The survivors were killed on gestation day
    29 and examined  post mortem. The uterus and ovaries were excised and
    examined, and the number of corpora lutea recorded. The number and
    position of live and dead fetuses, resorption sites, and the total
    number of implantation sites was also recorded. Live fetuses were

    removed, weighed, measured crown to rump, and examined for gross
    external and visceral abnormalities. Fetuses were then processed and
    examined for skeletal abnormalities. Cholinesterase activity was not
    measured.

         Although there was no statistically significant difference in
    survival between the treated and controls groups, no deaths occurred
    among the controls, four in the group at the low dose, three in the
    group at the intermediate dose, and two in the group at the high dose.
    In the last group, the deaths resulted from intrapulmonary intubation.
    Maternal weight gain was reduced at the doses of 50 and 100 mg/kg bw
    per day during treatment on days 6-18 of gestation. At days 12, 18,
    and 29, the mean body weight of the animals at the high dose was
    decreased in comparison with the controls. The mean number and percent
    of resorptions was slightly increased at doses > 50 mg/kg bw per
    day. There was no difference in fertility, number of corpora lutea,
    implantation sites, litter size, or fetal weight or length. No other
    signs of toxicity were seen in does or fetuses, nor was there any
    evidence of teratogenicity. The NOEAL was 25 mg/kg bw per day for
    maternal toxicity and 100 mg/kg bw per day for fetal toxicity, the
    former being based on decreased weight gain at the next highest dose
    and the latter on the absence of fetal toxicity at any dose (Siglin,
    1985). 

     (f)  Special studies

     (i)  Dermal and ocular irritation and dermal sensitization

         A single semi-occluded application of malathion (purity, 96-98%)
    to the skin of New Zealand white rabbits elicited slight to
    well-defined, transient dermal reactions, with very slight oedema in
    six animals and very slight erythema in five animals; the sixth had
    well-defined erythema. The skins were all normal by day 2 (Liggett &
    Parcell, 1985a). 

         Malathion (purity, 96-98%) produced mild conjunctival reactions
    in the eyes of New Zealand white rabbits. No damage to the cornea or
    iris was seen at any stage, and the eyes were normal after two days
    (Liggett & Parcell, 1985b).

         Malathion (purity, 96-98%) was tested in nine albino guinea-pigs;
    there were 10 controls. One treated animal with respiratory distress
    was killed  in extremis. There was no evidence of delayed contact
    hypersensitivity (Kynoch & Smith, 1985). 

     (ii)  Macrophage and mast cell function

          Repeated administration of malathion to female C57Bl/6 mice at a
    dose of 1 mg/kg bw per day increased macrophage function, while 0.1
    mg/kg bw per day caused mast cell degranulation (Rodgers & Xiong,
    1997).

     (iii)  Ocular function

         Malathion (purity, 98%) instilled into the eyes of Long-Evans
    rats had no effect on responses evoked by a visual pattern and
    produced no ophthalmological abnormality (Boyes, 1997).

     (iv)  Neurotoxicity

         The potential of malathion (purity, 93.6%) to induce delayed
    neuropathy was tested in white Leghorn hens. After determination of
    the oral LD50, the ability of atropine to antagonize the effects of
    malathion at doses greater than the LD50 was investigated. In the
    main study, 60 birds received malathion at a dose of 1000 mg/kg bw
    (1.3 times the unprotected LD50). They were given atropine sulfate
    subcutaneously at 10 mg/kg bw 1 h before administration of malathion
    and then at 30 mg/kg bw 15 min and 1, 3, and 5 h afterwards. A total
    of 39 birds died with clinical signs consistent with cholinesterase
    activity poisoning within 15 days. Three weeks after the first dose of
    malathion, the survivors were dosed again, this time at 850 mg/kg bw
    (1.1 times the LD50), with atropinization as above. A further seven
    birds died, but the survivors recovered completely. Positive controls
    were treated with tri- ortho-tolylphosphate at 500 mg/kg bw. The hens
    were observed daily; body weights and food consumption were recorded
    at the start of the study, and body weight was recorded thereafter at
    three-day intervals. All dead birds were examined with perfusion
    fixation, and the brain, spinal cord, and sciatic nerve were examined
    histologically No treatment-related histopathological changes were
    seen in the birds treated with malathion, whereas those treated with
    tri- ortho-tolylphosphate showed changes typical of
    organophosphate-induced delayed polyneuropathy in the spinal cord and
    sciatic nerve. Clinical signs of delayed polyneuropathy were seen only
    in the positive control birds (Fletcher, 1989).

         Groups of 12 retired laying Leghorn hens were given malathion
    orally at doses of 75, 150, or 300 mg/kg bw, and groups of 12
    Long-Evans rats (28 rats at the high dose) received 600, 1000, or
    2000 mg/kg bw. All received atropine pretreatment, and some received
    subsequent treatment with atropine. Clinical assessments were carried
    out. Cholinesterase and neuropathy target esterase activities were
    estimated, and sections of the medulla, cervical and lumber spinal
    cord, and branches of the tibial nerve were examined. Flaccid
    paralysis was seen in the hens at 300 mg/kg bw for about 24 h, but
    none died. There was no clinical indication of delayed polyneuropathy
    in the hens treated with malathion, whereas those given
    tri- ortho-tolylphosphate, mipafox, or diisopropylphosphorofluoridate
    developed typical behavioural signs of neuropathy. Malathion at a dose
    of 2000 mg/kg bw induced clinical signs consistent with cholinesterase
    poisoning in the rats, and gait changes were observed 14-21 days after
    administration at the highest dose. No treatment-related
    histopathological changes were seen in the birds or rats treated with
    malathion, whereas those treated with tri- ortho-tolylphosphate,
    mipafox, or diisopropyl phosphorofluoridate showed changes typical of
    organophosphate-induced delayed polyneuropathy. The activities of both

    acetylcholinesterase and neuropathy target esterase were inhibited by
    malathion. In the hens, brain acetylcholinesterase activity was
    inhibited by 17 ± 3% at the lowest dose of malathion and by 76 ± 1% at
    the highest; the corresponding inhibition of neuropathy target
    esterase activity was 0 ± 3% and 50 ± 22%. In the rats,
    acetylcholinesterase activity inhibition was 26 ± 6% at the lowest
    dose and 56 ± 2% at the highest; the corresponding figures for
    neuropathy target esterase inhibition were 19 ± 7% and 75 ± 5%, all
    compared with concurrent controls (Ehrich et al., 1995).

         Malathion and malaoxon produced nugatory inhibition of neuropathy
    target esterase activity in human neuroblastoma cells (3 and 1%,
    respectively) (Ehrich et al., 1994).

         The ratio of the IC50 value for neuropathy target esterase to
    that for acetylcholinesterase was 30 000 in murine neuroblastoma cells
    and 76 000 in human cells (Ehrich et al., 1997).

     (v)  Antidotes

         Malaoxon, the oxon analogue of malathion, inhibits cholinesterase
    activity by producing a dimethylphosphoryl derivative, which is
    susceptible to oxime-induced reactivation. Experimental evidence
    indicates that clinically significant reactivation occurs (Hobbiger,
    1973). Most authors have found significant reactivation with oximes,
    but there are notable exceptions. For example, Ganendran and
    Balabaskaran (1976) found little reactivation of malathion- and
    malaoxon-inhibited human whole-blood cholinesterase activity. Similar
    results were obtained for acetylcholinesterase activity in goat brain
    (Cheema et al., 1989).

         The efficacy of four pyridinium oximes, trimedoxime, obidoxime,
    pralidoxime, and HI-6, in the treatment of poisoning by malathion
    (purity, 96%) was tested in male Wistar rats, which were given
    malathion at twice the LD50, as determined experimentally during the
    study, and treated with 30 mol/kg bw of trimedoxime, obidoxime, or
    HI-6 or 60 mol/kg bw of pralidoxime; atropine and diazepam therapy
    were also used. Of the oximes, obidoxime was the most effective,
    followed by trimoxime, and then pralidoxime and HI-6, which were
    equally effective; however, better survival was achieved with HI-6 at
    a dose of 150 mol/kg bw than with the other regimes. Thus, malathion
    posoning can be treated with mono- and bis-pyridinium oximes
    (Jokanovic & Maksimovic, 1995).

         Malathion (50% emulsifiable concentrate) was administered at a
    dose of 100 mg/kg bw or at a minimally lethal dose of 125 mg/kg bw to
    buffalo calves  (Bubalus bubalis). Pralidoxime methiodide combined
    with atropine was reported to reverse the clinical evidence of
    toxicity (Gupta, 1984). 

         Pralidoxime chloride or diacetyl monoxime at a dose of 100 mg/kg
    bw intraperitoneally reversed the rise in blood glucose observed after
    injection of malathion at 500 mg/kg bw to female albino rats, provided
    the oximes were given immediately after the malathion. When given 15
    min later, the antidotes were ineffective (Agarwal & Matin, 1981). 

         Obidoxime reversed malaoxon-induced inhibition of cholinesterase
    activity in isolated rat diaphragm and restored the ability to sustain
    tetany; moreover, obidoxime at 20 mg/kg bw together with atropine
    raised the LD50 in OF mice by 5.1-fold, the comparable figure for
    atropine alone being 1.7-fold (Abraham & Edery, 1976). 

         Obixodime has been used successfully in treating malathion
    poisoning in humans (Dive et al., 1994; see below).

    3.  Observations in humans

         Malathion and ethyl- para-nitrophenyl thionobenzenephosphonate
    (purity of each unspecified) were tested in volunteer male prisoners
    aged 23-36 years. In phase I of the study, four samples of blood were
    taken during two weeks before the start of the study for measurements
    of plasma and erythrocyte cholinesterase activity, and then malathion
    was administered at a dose of 8 mg/day to five subjects for 32 days.
    Phase II was begun three weeks after completion of phase I. On the two
    days before its start, samples of plasma and washed erythrocytes were
    taken for measurements of cholinesterase activity, and then malathion
    was administered to the same five subjects at a dose of 16 mg/day for
    47 days. In phase III, five new subjects were selected; plasma and
    erythrocyte cholinesterase activity was determined in blood samples
    drawn twice weekly for 36 days, before administration of malathion at
    a dose of 24 mg/day for 56 days. 

         During phase I, no clinical effects were observed, and there were
    no changes in blood counts or the results of urinalysis. Furthermore,
    no significant depression of plasma or erythrocyte cholinesterase
    activity was observed in any subject. Similarly, no clinical effects
    were observed in phase II. In phase III, depression of plasma
    cholinesterase activity was observed two weeks after the first
    administration of malathion, the maximum depression being 25%, seen
    three weeks after cessation of treatment; erythrocyte
    acetylcholinesterase activity was depressed to the same extent. The
    NOAEL was 6 mg/day, approximately equal to 0.27 mg/kg bw per day. No
    potentiation of malathion by ethyl- para-nitrophenyl
    thionobenzenephosphonate was observed (Moeller & Rider, 1962). 

         An epidemic of poisoning of spraymen in Pakistan was attributed
    largely to contaminants, particularly iso-malathion, in the
    formulation of malathion used (Baker et al., 1978). 

         There are numerous case reports of individual poisoning. Thus,
    Dive et al. (1994), reported an instance in which an elderly woman
    consumed about 100 ml of a garden preparation containing 15% malathion
    in isopropyl alcohol. The preparation also contained
    isopropylmalathion and  O,O,S-trimethylphosphorothioate. A typical
    cholinergic crisis was followed by cardiac, pulmonary, neurological,
    and renal manifestations, and the patient was treated with atropine
    and obidoxime. The cardiac manifestations included arrhythmia and
    conduction disturbances. Mild interstitial pulmonary fibrosis was
    observed in a lung biopsy sample.

         Matsushita et al. (1985) reported allergic contact dermatitis in
    people exposed to organophosphorus insecticides including malathion. 

         Thomas et al. (1990) reported a study of women exposed to
    malathion during aerial spraying of large areas of the San Francisco
    Bay area, USA, in 1981-82. A number of associations were found, of
    which one, congenital gastrointestinal anomalies, remained
    statistically significant after control for confounders. 

         An episode of epidemic hysteria was reported at an elementary
    school in Arizona, USA, in response to the smell of malathion (Baker &
    Selvey, 1992).

         During a campaign to eradicate Mediterranean fruit flies with a
    pesticide based on malathion, a number of cases of urticaria,
    angioneurotic oedema, and non-specific rashes were reported. Of 10
    subjects that received a patch test, none responded. One case of
    possible immediate reaction to malathion bait was reported (Schanker
    et al., 1992).

         No case of organophosphate-induced delayed polyneuropathy due to
    malathion has been reported in humans.

    Comments

         Malathion is rapidly absorbed, biotransformed, and excreted,
    predominantly in the urine but also in the faeces, largely as its two
    monocarboxylic acids and the dicarboxylic acid.

         The oral LD50 values for malathion in laboratory rodents were
    1000-10 000 mg/kg bw, the observed differences probably being due to
    impurities. The most recent LD50 values tend to be higher. The
    cholinesterase-inhibiting metabolite of malathion, malaoxon, has much
    lower oral LD50 values of 100-220 mg/kg bw. WHO has classified
    malathion as slightly hazardous (WHO, 1996).

         In a study of neurotoxicity in rats receiving single doses of 0,
    500, 1000, or 2000 mg/kg bw, there was no NOAEL, as clinical signs
    were present at all doses. In a 13-week study of neurotoxicity, also
    in rats, at dietary concentrations of 0, 50, 5000, or 20 000 ppm, the
    NOAEL was 5000 ppm, equal to 350 mg/kg bw per day, on the basis of
    inhibition of brain acetylcholinesterase at the highest dose.

         In a 30-day study of toxicity in rats receiving malathion in the
    diet at concentrations of 0, 50, 100, 500, 10 000, or 20 000 ppm, the
    NOAEL was 500 ppm, equal to 52 mg/kg bw per day, on the basis of
    increased liver weight and histopathological changes in the liver
    (periportal hepatocyte hypertrophy) at the next highest dose.

         In a 90-day study of toxicity in rats, malathion was given at
    dietary concentrations of 0, 100, 500, 5000, 10 000, or 20 000 ppm.
    The NOAEL was 500 ppm, equal to 34 mg/kg bw per day, on the basis of
    decreased mean corpuscular volume and mean corpuscular haemoglobin,
    increased liver weights and relative kidney weights, and chronic
    nephropathy in males and decreased mean cell volume, hepatocyte
    hypertrophy, and increased relative kidney weight in females at the
    next highest dose. 

         A 21-day study of dermal toxicity was carried out in which
    rabbits were treated with malathion at doses of 0, 50, 300, or 1000
    mg/kg bw per day for 6 h per day, five days per week. The NOAEL was
    300 mg/kg bw per day on the basis of inhibition of brain
    acetylcholinesterase activity at the highest dose. 

         In a 28-day study of toxicity in dogs, malathion was fed in
    gelatin capsules at doses of 0, 125, 250, or 500 mg/kg bw per day for
    28 days. There was no NOAEL because of clinical signs at all doses.

         In a one-year study of toxicity in dogs, malathion was
    administered orally in capsules at doses of 0, 62.5, 125, or 250 mg/kg
    bw per day on seven days per week. The NOAEL was 125 mg/kg bw per day
    on the basis of body-weight depression and changes in haematological
    and clinical chemical parameters at the highest dose.

         A number of long-term studies of toxicity and carcinogenicity
    have been carried out on malathion in both rats and mice. The earlier
    ones were reviewed by a working group convened by the IARC, which
    concluded that the available data did not provide evidence that
    malathion was carcinogenic.

         In an 18-month study in mice, malathion was administered at
    dietary concentrations of 0, 100, 800, 8000, or 16 000 ppm. The NOAEL
    was 800 ppm, equal to 140 mg/kg bw per day, on the basis of inhibition
    of brain acetylcholinesterase activity at termination and an increased
    incidence of liver adenomas in animals of each sex at the next highest
    dose. 

         In a two-year study in rats, dietary concentrations of 0, 100,
    1000, or 5000 ppm were used. The NOAEL was 100 ppm, equivalent to 5
    mg/kg bw per day, on the basis of reduced erythrocyte
    acetylcholinesterase activity and body weight. In another long-term
    study in rats, malathion was given at doses of 0, 100/50, 500, 6000,
    or 12 000 ppm for two years. The NOAEL was 500 ppm, equal to 29 mg/kg
    bw per day, on the basis of decreased survival and body-weight gain,
    changes in haematological parameters, decreased brain

    acetylcholinesterase activity, increased g-glutamyl transpeptidase
    activity, increased liver, kidney, and thyroid/parathyroid weights,
    and changes in the olfactory epithelium at the next highest dose.

         Numerous tests have been carried out for genotoxicity both  in 
     vitro and  in vivo. Most of the evidence indicates that malathion
    is not genotoxic, although some studies indicate that it can produce
    chromosomal aberrations and sister chromatid exchange  in vitro. 
    There was no evidence that malathion induces chromosomal aberrations
     in vivo. Malaoxon did not induce reverse mutation in bacteria, but
    it caused sister chromatid exchange in two tests in mammalian cells
    and induced sex-linked recessive lethal mutation in  Drosophila in 
     vivo. The four common impurities of malathion, isomalathion,
     O,O,S-trimethyl phosphorothioate,  O,S,S-trimethyl
    phosphorodithioate, and  O,O,O-trimethyl phosphorothioate, did not
    induce reverse mutation in bacteria. The Meeting concluded that
    malathion is not genotoxic.

         A number of studies of reproductive toxicity have been carried
    out, only some of which showed NOAELs. In a study in rats, malathion
    was administered by gavage to groups of pregnant animals on days 6-15
    of gestation at doses of 0, 200, 400, or 800 mg/kg bw per day. The
    NOAEL was 400 mg/kg bw per day on the basis of maternal toxicity at
    the highest dose; no fetal toxicity was observed. 

         Malathion was administered orally at doses of 0, 25, 50, or 100
    mg/kg bw per day to groups of pregnant rabbits on days 6-18 of
    gestation. The NOAELs were 25 mg/kg bw per day for maternal toxicity
    and 100 mg/kg bw per day for fetal toxicity; teratogenicity was not
    seen at any dose.

         A two-generation study was undertaken in rats in which malathion
    was given at dietary concentrations of 0, 550, 1700, 5000, or 7500
    ppm. The NOAEL was 7500 ppm, equal to 600 mg/kg bw per day, for
    reproductive toxicity and 1700 ppm, equal to 130 mg/kg bw per day, for
    developmental toxicity, the latter being based on reduced pup weights.

         Two studies on the neurotoxicity of malathion in hens were
    reviewed. In neither was there evidence that malathion can cause
    delayed neuropathy, although some inhibition of neuropathy target
    esterase activity was found in the brains of birds at 2000 mg/kg bw. 

         In a study in volunteers with doses of 8, 16, or 24 mg of
    malathion per day, the NOAEL was 16 mg per day (equivalent to 0.27
    mg/kg bw per day) on the basis of inhibition of plasma and erythrocyte
    cholinesterase activity. Several cases of exposure to impure malathion
    have been reported, none of which resulted in delayed neuropathy.

         An ADI of 0-0.3 mg/kg bw was established on the basis of the
    NOAEL of 29 mg/kg bw per day in the two-year study of toxicity and
    carcinogenicity in rats, with a safety factor of 100. This ADI is
    supported by the NOAEL of 25 mg/kg bw per day in the study of
    developmental toxicity in rabbits. The alternative approach of basing
    the ADI on the study in humans was not taken, as the study was old and
    the material was therefore likely to contain toxic impurities.

    Toxicological evaluation

     Levels that cause no toxic effect

         Mouse:    800 ppm, equal to 140 mg/kg bw per day (18-month study
                   of toxicity and carcinogenicity)

         Rat:      500 ppm, equal to 29 mg/kg bw per day (two-year study
                   of toxicity and carcinogenicity)

                   1700 ppm, equal to 130 mg/kg bw per day (study of
                   reproductive toxicity)

                   400 mg/kg bw per day (maternal toxicity in a study of
                   developmental toxicity)

         Rabbit:   25 mg/kg bw per day (maternal toxicity in a study of
                   developmental toxicity)

         Dog:      125 mg/kg bw per day (one-year study of toxicity)

         Human:    0.3 mg/kg bw per day (47-day study of toxicity)

     Estimate of acceptable daily intake for humans

         0-0.3 mg/kg bw

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

         Further observations in humans

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        Toxicological criteria for setting guidance values for dietary and non-dietary exposure to malathion

                                                                                                                            

    Human exposure       Relevant route , study type, species             Results, remarks
                                                                                                                            

    Short-term           Oral, toxicity, rat                              LD50 = 1000-11 000 mg/kg bw
    (1-7 days)           Inhalation, toxicity, rat                        LC50 > 5.2 mg/L
                         Dermal irritation, rabbit                        Mildly irritating
                         Ocular irritation, rabbit                        Mildly irritating
                         Dermal sensitization, guinea-pig                 Not sensitizing

    Medium-term          Repeated oral, 90 days, rat                      NOAEL = 34 mg/kg bw per day: systemic toxicity
    (1-26 weeks)         Repeated dermal, 21 days, rabbit                 NOAEL = 300 mg/kg bw per day: decreased brain 
                                                                          acetylcholinesterase activity
                         Repeated oral, developmental toxicity, rabbit    NOAEL = 25 mg/kg bw per day: maternal toxicity;  
                                                                          NOAEL = 100 mg/kg bw per day: fetal toxicity
                         Repeated oral, reproductive toxicity, rat        NOAEL = 600 mg/kg bw per day: no parental toxicity; 
                                                                          NOAEL = 130 mg/kg bw per day: developmental 
                                                                          toxicity

    Long-term            Repeated oral, 2 years, rat                      NOAEL = 29 mg/kg bw per day: decreased survival,  
    (> 1 year)                                                            reduced body weight, decreased brain 
                                                                          acetylcholinesterase activity
                                                                                                                            
    

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    See Also:
       Toxicological Abbreviations
       Malathion (ICSC)
       Malathion (FAO Meeting Report PL/1965/10/1)
       Malathion (FAO/PL:CP/15)
       Malathion (FAO/PL:1967/M/11/1)
       Malathion (JMPR Evaluations 2003 Part II Toxicological)
       Malathion (FAO/PL:1968/M/9/1)
       Malathion (FAO/PL:1969/M/17/1)
       Malathion (AGP:1970/M/12/1)
       Malathion (WHO Pesticide Residues Series 3)
       Malathion (WHO Pesticide Residues Series 5)
       Malathion (Pesticide residues in food: 1977 evaluations)
       Malathion (Pesticide residues in food: 1984 evaluations)
       Malathion (IARC Summary & Evaluation, Volume 30, 1983)