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    MEVINPHOS

    T. C. Marrs
    Department of Health, Elephant and Castle, London, United Kingdom

    Explanation
    Evaluation for acceptable daily intake
       Biochemical aspects
          Absorption, distribution, and excretion
          Biotransformation
       Toxicological studies
          Acute toxicity
          Short-term toxicity
          Long-term toxicity and carcinogenicity
          Reproductive toxicity
          Developmental toxicity
          Genotoxicity
          Special studies
             Dermal and ocular irritation and dermal sensitization
             Neurotoxicity
       Observations in humans
    Comments
    Toxicological evaluation
    References

    Explanation

         Mevinphos was evaluated for toxicological effects by the JMPR in
    1963 and 1965 (Annex 1, references 2 and 4); in neither case was an
    ADI assigned. An ADI of 0-0.0015 mg/kg bw was established in 1972
    (Annex 1, reference 18). The toxicology of the compound was reviewed
    at the present Meeting within the CCPR periodic review programme. This
    monograph summarizes data not previously reviewed and relevant data
    from the previous monograph on mevinphos (Annex 1, reference 19).

    Evaluation for acceptable daily intake

    1.  Biochemical aspects

         Mevinphos consists of two  cis/trans isomers of methyl
    3-(dimethoxyphosphinyloxy)-2-butenoate. Commercial preparations vary
    in the relative amounts of each, but most contain about 65-75% alpha
    and 10-20%  isomer (Figure 1).

    Figure 1.  Isomers of mevinphos

                                  O
                                  "
                          H3C     C-OCH3
                             \   /
                          O   C=C
                          "  /   \
                     CH3O-P-O     H
                          '
                          OCH3

                   alpha-; E-;  cis-mevinphos



                          H3C     H
                             \   /
                          O   C=C
                          "  /   \
                     CH3O-P-O     C-OCH3
                          '       "
                          OCH3    O


                    -; Z-;  trans-mevinphos

    (a)  Absorption, distribution, and excretion

         The penetration of 14C-mevinphos (purity, 96%; 73% alpha and
    15%  isomer) diluted with water across the nonoccluded skin of
    Crl:CD(SD)BR rats was examined  in vivo. The doses were 5, 30,
    or 150 g per animal (0.4, 2.5, and 12.5 g/cm2 of skin). The
    radiochemical purity of the labelled compound was 87%; this was
    repurified to > 96%. Absorption, measured as the amount in the skin
    and that penetrating the skin, was 47-48% of the applied dose; of
    this, 13-17% crossed the skin (Jeffcoat & Coleman, 1993).

         After a preliminary study in which it was found that substantial
    amounts of label were expired, the absorption, distribution, and
    excretion of mevinphos (75% alpha and 15%  isomer) was studied in
    groups of five male and five female Sprague-Dawley (Crl:CD BR) rats.

    Either a single oral dose of 14C-mevinphos at 0.15 or 1.5 mg/kg bw;
    multiple doses of 0.15 mg/kg bw, only the last (16th) dose being
    radiolabelled; or a single intravenous dose of 0.15 mg/kg bw were
    given. In all cases, the label was rapidly absorbed, transformed, and
    excreted, predominantly by exhalation, with 77% in the breath of
    males and 78% in the breath of females after the single oral dose of
    0.15 mg/kg bw, and only 14% in the urine over 24 h, mostly within 8 h.
    At the higher oral dose, 61-62% of the label appeared in the breath
    and 23% in the urine. After the intravenous dose, about 71% of the
    label appeared in the breath of animals of each sex and 16 and 17% in
    the urine of males and females, respectively. After administration of
    16 daily oral doses, 75% of the administered dose was found in the
    expired air of males and 77% in that of females, urinary excretion
    being 16 and 19%. In all these studies, almost all of the radiolabel
    (85-96%) was eliminated within 24 h as carbon dioxide and in the
    urine; < 1.3% was excreted in the faeces. Thus, mevinphos was almost
    completely absorbed (Reddy  et al., 1991).

    (b)  Biotransformation

         In the study of Reddy  et al. (1991), mevinphos was metabolized
    primarily to carbon dioxide, and only traces of other volatile
    materials were present. High-performance and thin-layer liquid
    chromatography of the urine showed four major peaks, representing
    unmetabolized alpha isomer of mevinphos and the alpha isomers of
    mevinphos acid and desmethyl mevinphos. A fourth peak may have
    represented mevinphos diacid.

         The proposed metabolic pathway for mevinphos in Sprague-Dawley
    rats is shown in Figure 2.

    2.  Toxicological studies

    (a)  Acute toxicity

         The results of studies of the acute toxicity of mevinphos are
    shown in Table 1.

    FIGURE 6

        Table 1.  Acute toxicity of mevinphos in experimental animals

                                                                                                                                      

    Species               Strain                 Sex          Route          Purity         LD50 (mg/kg bw)           Reference
                                                                               (%)         or LC50 (mg/litre)
                                                                                                (95% CI)
                                                                                                                                      

    Mouse        Swiss Webster                  Male         Dermal            99              12 (6-24)          Skinner & Kilgore
                                                             (feet)                                               (1982)
    Rat          Sherman                        Male         Oral              NR                 6.1             Gaines (1969)
                                                Female                                            3.7
    Rat          Sprague-Dawley                 Male         Oral              NR            4.1 (3.5-5.0)        Deenihan (1985)
                                                Female                                       2.2 (1.8-2.6)
    Rat          Sprague-Dawley-derived CD      Male         Oral             97.7               3.5a             Auletta (1988a)
                                                Female                                       2.3 (1.0-3.6)
    Rat          Albino HSD:SD                  Male         Oral           Unknownb              > 5             Kuhn (1994)
                                                Female                                            > 5
    Rat          Sherman                        Male         Dermal            NR                 4.7             Gaines (1969)
                                                Female                                            4.2
    Rat          Sprague-Dawley Crl:CD BR       Male         Dermal            90                 >20             Trimmer (1989)
                                                Female                                            >20
    Rat          Sprague-Dawley CD              Male         Inhalationc       100                12              Hoffman (1988)
                                                Female                                            7.3
    Rabbit       New Zealand white              Male,        Dermal            NR             57 (38-86)          Deenihan (1985)
                                                female
    Rabbit       New Zealand white              Male         Dermal           99.3            51 (31-71)          Auletta (1988b)
                                                Female                                        60 (23-97)
    Chicken      White Leghorn pullets          Female       Oral          approx. 97         11 (3.2-19)         Barrett (1988)
                                                                                                                                      

    CI, confidence interval; NR, not reported
    a    CI could not be calculated owing to distribution of deaths
    b    Phosdrin 4 EC
    c    4-h exposure; only 3 h at highest dose as all animals had died
        (b)  Short-term toxicity

    Mice

         In a three-month range-finding study, groups of 10 male and 10
    female CD-1 mice were fed diets containing mevinphos (66.5% alpha,
    21.2%  isomer) at 0, 0.5, 1, 2, or 10 ppm, equal to 0, 0.1, 0.2, 0.4,
    and 2 mg/kg bw per day for males and 0, 0.1, 0.3, 0.5, and 2.7 mg/kg
    bw per day for females. Clinical observations, body weight, and food
    consumption were reported before treatment and weekly after the start
    of exposure, and plasma and erythrocyte cholinesterase activities
    were measured in five animals of each sex per group at week 7 and
    at termination. After three months, the animals were killed and
    autopsied, and brain acetylcholinesterase activity was measured in
    five animals of each sex per group. Organs from controls and animals
    at the high dose were examined grossly, and selected tissues were
    examined microscopically. Body weight and food consumption were
    similar in all groups, and no deaths occurred; clinical parameters
    were similar in all groups. Plasma cholinesterase activity was
    decreased by 37-49% in animals of each sex at 2 and 10 ppm at week 7.
    At termination, similar findings were seen in males, but the decreased
    plasma cholinesterase activity in females was confined to those at
    10 ppm. Brain acetylcholinesterase activity was decreased by 16 and
    22% in males and females at 10 ppm, respectively, in comparison with
    controls. The NOAEL was 2 ppm, equal to 0.4 mg/kg bw per day, on the
    basis of inhibition of brain acetylcholinesterase activity at 10 ppm
    (Atkinson, 1990).

    Rats

         Groups of 10 Sprague-Dawley Crl:CD BR rats received mevinphos
    (74.5% alpha, 15.1%  isomer) by gavage for 90 days at doses of active
    ingredient of 0.056, 0.56, 1.1, or 1.7 mg/kg bw per day for males and
    0.011, 0.056, 0.56, or 0.84 mg/kg bw per day for females. Five males
    at the two highest doses died, and the highest dose was decreased to
    1.1 mg/kg bw per day on day 36; the groups at the two highest doses
    were then combined for most statistical purposes. Additionally, one
    female at 0.56 mg/kg bw per day died before scheduled termination.
    Clinical signs, including pinpoint pupils, oral and ocular discharges,
    and tremors were seen at doses > 0.56 mg/kg bw per day in animals
    of each sex. No statistically significant differences in body weight
    or food consumption were noted. Inhibition of plasma cholinesterase
    activity > 15% was seen at week 7 and terminally in males at doses
    > 0.56 mg/kg bw per days and in females at doses > 0.056 mg/kg
    bw per day. Brain acetylcholinesterase activity was inhibited by
    > 15% at termination in animals of each sex at doses > 0.56 mg/kg
    bw per day. No significant depression of erythrocyte acetyl-
    cholinesterase activity was seen. There was a dose-related increase
    in mean cholesterol levels, which were statistically significantly
    increased in males at the high dose. No statistically significant

    differences in absolute or relative organ weights were seen between
    groups, but a dose-related trend in increased relative liver weights
    was seen in animals of each sex. Slight vacuolation in centrilobular
    and midzonal hepatocytes was seen in two male rats at the highest
    dose. The NOAEL was 0.056 mg/kg bw per day, on the basis of clinical
    signs and depressed brain acetylcholinesterase activity at higher
    doses (Keefe, 1992).

    Dogs

         Gelatine capsules containing mevinphos (75.1% alpha, 11.8% 
    isomer) in corn oil were given to groups of five male and five female
    beagle dogs at doses of 0 or 0.5 mg/kg bw per day and to four males
    and four females at 0.025 or 0.25 mg/kg bw per day for one year. No
    deaths occurred during the study. The only clinical sign attributable
    to the test material was a higher prevalence of vomiting in the dogs
    at the high dose than in the controls. No significant differences in
    body weight or food consumption were noted, and no treatment-related
    changes were seen at ophthalmoscopic examination at weeks 12, 26, and
    52. Blood was taken before treatment and at weeks 6, 12, 39, and 51
    for laboratory analyses. No biologically significant haematological or
    biochemical changes were seen, other than changes in cholinesterase
    activity. Plasma and erythrocyte cholinesterase activities were
    determined on blood samples taken before the start of treatment, 3 h
    after dosing at 4, 12, 39, and 51 weeks, and before dosing at weeks
    39 and 51. Brain acetylcholinesterase activity was measured at
    termination of the study. At many of these time intervals, both
    erythrocyte and plasma cholinesterase activities were depressed,
    particularly at the two higher doses. In dogs at the lowest dose, a
    depression > 15% was seen in erythrocyte enzyme activity at week 25
    in males and females, at week 39 in males before treatment and in
    females before and after treatment, and at week 51 in males before and
    after treatment and in females after treatment. At this dose, plasma
    cholinesterase activity was depressed by > 15% at 39 and 51 weeks in
    females after treatment. Statistically and biologically significant
    inhibition of brain acetylcholinesterase activity was observed only in
    males at the highest dose, in which the activity was 77% of that in
    concurrent controls. Higher absolute thyroid/parathyroid weights
    were observed in females at the highest dose and higher relative
    thyroid/parathyroid weights in females at the intermediate dose. No
    associated histopathological abnormality was discerned, and these
    findings are considered not to be significant. No treatment-related
    pathological finding was seen at autopsy. The NOAEL was thus
    0.25 mg/kg bw per day, on the basis of clinical signs and a reduction
    in brain acetylcholinesterase activity at the highest dose (Kangas,
    1995).

    (c)  Long-term toxicity and carcinogenicity

    Mice

         On the basis of a range-finding study, mevinphos (purity, 87.7%;
    66.5% alpha, 21.2%  isomer) was administered to four groups of 50
    CD-1 mice of each sex at dietary concentrations providing doses of 0,
    1, 10, or 25 ppm, equal to 0, 0.1, 1.5, and 3.7 mg/kg bw per day for
    males and 0, 0.1, 1.9, and 4.8 mg/kg bw per day for females, for 18
    months. Physical examinations were performed each week and body weight
    and food consumption before the start of the study, weekly thereafter
    for 13 weeks on alternate weeks until week 26, and thence monthly.
    Blood smears for evaluating the differential leukocyte count and
    erythrocyte morphology were taken from 10 animals of each sex per
    group at 12 and 18 months. Treatment had few effects, but the survival
    rate was somewhat reduced in males at the low dose, with only 20
    survivors, in comparison with 27 male controls, 26 at the middle dose,
    and 24 at the high dose. In females, the mortality rate was similar in
    all groups (36-40%). During the first three months of the study, the
    mean body weights of animals at the highest dose were lower than those
    of controls; this effect lasted up to week 16 in males and week 12 in
    females. Females at the two highest doses had lower leukocyte counts
    than controls at 18 but not at 12 months. No treatment-related gross
    or microscopic pathological changes were seen, nor were there
    treatment-related changes in organ weights. Although tumours were
    observed in a number of organs, especially the liver and lungs, there
    was no evidence of treatment-related neoplasia in any treated group.
    Cholinesterase activity was not measured in this study, as it had
    been evaluated in the range-finding study, in which the NOAEL for
    inhibition of brain acetylcholinesterase activity was 2 ppm. The NOAEL
    in the main study was 25 ppm, equal to 3.7 mg/kg bw per day, as the
    transient effect on body weight in mice at the high dose can be
    ignored (Atkinson, 1989).

    Rats

         Groups of 80 male and 80 female Crl:CD BR rats were given
    mevinphos (purity, 85.7%; 74.9% alpha, 10.8%  isomer) by gavage in
    water on five days per week for two years at doses of 0, 0.025, 0.35,
    or 0.70 mg/kg bw per day. In females, the high dose was reduced to
    0.60 mg/kg bw per day on day 83 of the study because of signs of
    acute toxicity. Ten rats from each group were killed at 12 months for
    histopathological examination, 10 rats from each group were used for
    clinical chemical determinations, and a further 10 were used to
    measure cholinesterase activity and were killed at 104 weeks. Clinical
    examinations were conducted weekly, and body weights were recorded
    before the start of the study, at the start of dosing, and thereafter
    weekly for 13 weeks and every four weeks afterwards. Food consumption
    was also measured weekly for 13 weeks and every four weeks thereafter.
    Clinical chemical, haematological, and urinary analyses were undertaken

    and plasma and erythrocyte cholinesterase activities were measured
    before treatment, at 3, 6, 1,2 and 18 months, and at termination. Brain
    acetylcholinesterase activity was measured at the interim kill and at
    the end of the study, but there were too few survivors at the end of
    the study for useful intergroup comparisons to be made. Ophthalmoscopic
    examinations were done before the start of the study and before
    termination. Full histopathological examinations were performed on the
    10 animals from each group killed at 12 months and on the survivors at
    two years. Selected organs were weighed and examined microscopically.

         Less than 40% of the rats survived to termination at 104 weeks,
    and there was a dose-related reduction in survival in males, the rate
    being clearly reduced at the highest dose; there were no significant
    differences in mortality among female rats. Clinical signs typical of
    anticholinesterase poisoning, including tremors, were observed after
    administration of both the medium and high doses. No treatment-related
    changes in body weight, food consumption, or haematological, clinical
    chemical, urinary, or ophthalmoscopic parameters were discerned,
    except for cholinesterase activity. Plasma, erythrocyte, and brain
    cholinesterase activity was diminished in the animals at the middle
    and high doses but not in those at the low dose; decreases in
    erythrocytic acetylcholinesterase activity > 20% were not observed
    in animals of either sex at any dose, but a depression of 20% was
    observed at six months in females treated with mevinphos at 0.60 mg/kg
    bw per day. Although inhibition of plasma cholinesterase activity was
    not seen at the low dose, reductions of 38-51% were seen in males
    at the middle dose and 47-61% in males at the high dose; plasma
    cholinesterase activity was depressed by 50-67% in females at the
    middle dose and 66-71% at the high dose. Brain acetylcholinesterase
    activity was depressed by 27% in males at the middle dose, 53% in
    males at the high dose, 43% in females at the middle dose, and 55% in
    females at the high dose at the interim kill. No treatment-related
    effects were seen on histopathological examination. A low incidence of
    combined incidental and fatal hepatocellular adenomas was seen (0/67,
    1/67, 1/69, and 2/68 in males and 1/70, 0.66, 0/67, and 3/67 in
    females), which gave a dose-response relationship. One female at
    the high dose had a hepatocellular carcinoma, giving a significant
    dose-response relationship for all hepatocellular tumours. The numbers
    involved were small, there was no dose-response relationship for liver
    carcinomas alone or for adenomas and carcinomas combined in males, and
    the incidence was well within that of historical controls. Hence, it
    was concluded that there was no evidence of any treatment-associated
    tumours. The NOAEL was 0.025 mg/kg bw per day on the basis of
    inhibition of brain acetylcholinesterase activity and clinical signs
    at doses > 0.35 mg/kg bw per day (Plutnick, 1994).

    (d)  Reproductive toxicity

         In a two-generation study, groups of 35 male and 35 female Crl:CD
    BR (Sprague-Dawley) VAF/Plus rats, seven weeks of age, received
    mevinphos (purity, 89.6%; 74.5% alpha, 15.1%  isomer) in water by
    gavage at doses of 0, 0.05, 0.1, or 0.5 mg/kg bw. Dosing was adjusted
    to allow for the low purity of the material. The F0 rats were dosed
    daily for 10 weeks before being assigned randomly, within the dose
    groups, into mating pairs at least 11 weeks after the start of dosing.
    Dosing was continued during mating, and the F0 females continued to
    be treated during gestation and lactation until weaning of the F1
    litter 21 days  post partum. Offspring were counted, sexed, weighed
    (excluding postnatal day 0), and examined externally on postnatal days
    0, 1, 4, 7, 14, and 21; litters were culled to four males and four
    females. The F1 litters were dosed from 28 days  post partum for at
    least 11 weeks before mating and also during the mating period. F1
    females were dosed during gestation and lactation until weaning on day
    21 after birth. Clinical observations were made and body weights
    measured before selection of the F0 animals on the first day of
    dosing and thereafter weekly in both generations. Observations were
    made more frequently in the F0 generation during gestation (days 0,
    7, 14, and 21) and on the same days  post partum. Erythrocyte,
    plasma, and brain cholinesterase activity was measured in all animals
    that survived to termination. Necropsies were performed on all
    mated animals, all decedent pups, and pups killed  in extremis.
    Histopathological examinations were performed only on the controls
    and animals at the high dose, except that the ovaries of all F1
    females were examined.

         Treatment-related clinical signs were seen in F0 females at the
    high dose, which included ataxia, fine or coarse tremors, pinpoint
    pupils, and oral discharge. The growth of F1 animals of each sex was
    significantly reduced, and some reduction in the body weights of F1
    males and females at the high dose was observed before weaning on
    postnatal days 4-21. A reduction in the body weights of F1 male
    offspring at the high dose may represent continuation of the reduction
    in the F0 males before weaning. The growth of F2 males at the high
    dose was also reduced. Cholinesterase inhibition was observed in both
    generations but was generally more severe in F1 animals. Significant
    inhibition of brain acetylcholinesterase activity was observed in
    animals of each sex at the high dose, while no significant inhibition
    of erythrocyte cholinesterase activity was seen at any dose; inhibition
    of plasma cholinesterase activity extended to animals at the middle
    dose and to those at the low dose in the F1 generation. F1 animals
    at the high dose showed a reduction in the absolute weight of the
    testes or epididymides (12%) and in the relative ovarian weight
    (17%). The former may be a reflection of the lower total body weight
    of these animals, but the F1 males in all treated groups had lower
    mean mating and fertility indices than controls; although these

    effects were not statistically significant, they may be associated
    with the lower testicular weight observed. The effect on the ovaries
    may be a treatment-related effect, as some female rats at the highest
    dose had fewer or absent corpora lutea. The frequency of this
    pathological observation did not, however, attain statistical
    significance, and there were no significant effects on female
    fecundity or fertility indices; moreover, the live litter sizes of
    the animals at the high dose and the controls were comparable. The
    NOAEL was 0.1 mg/kg bw per day on the basis of the presence of clinical
    signs and reduced brain acetylcholinesterase activity in animals at
    the highest dose, at which impaired growth, impaired fertility
    indices, and lower testicular weights were seen in males and lower
    ovarian weights in females (Beyer, 1991b).

    (e)  Developmental toxicity

    Rats

         Mevinphos (65.5% alpha isomer) was administered to four groups of
    24 mated CD rats by gavage in water. One group served as controls,
    while the other groups were given mevinphos at daily doses of 0.2,
    0.75, or 1.2 mg/kg bw per day on days 6-15 of gestation. A high
    mortality rate (29.2%) was observed in rats at the high dose, which
    was therefore terminated and a new group receiving 1 mg/kg bw per day
    was added. Females were weighed and examined at regular intervals,
    while food consumption was recorded on days 0-6, 6-10, 10-15, and
    15-20 of gestation. The animals were killed on day 20 of gestation and
    examined at autopsy; corpora lutea and uterine implantations were
    counted, and fetuses were weighed, sexed, and examined grossly for
    malformations. One-half of the fetuses in each litter were processed
    for visceral examination and the remainder stained for evaluation of
    skeletal changes. Deaths were observed only in the prematurely
    terminated group at 1.2 mg/kg bw per day. A dose-related decrease in
    mean weight gain was seen during days 6-15 of gestation, but none of
    the decreases attained statistical significance. Clinical signs of
    cholinergic poisoning (tremors) were seen in about half the animals at
    the high dose, and excessive salivation was seen in four animals in
    that group. No indication of maternal toxicity was seen in the other
    groups, apart from tremor in two rats at the middle dose on day 15.
    There were no adverse effects on uterine implantation, fetal weight,
    fetal sex distribution, or the external appearance of fetuses, and
    there were no visceral or skeletal abnormalities in any treated group.
    The NOAEL for maternal toxicity was 0.75 mg/kg bw per day on the basis
    of clinical signs at the next highest dose; the NOAEL for developmental
    toxicity was 1.0 mg/kg bw per day, the highest dose tested (Schroeder &
    Daly, 1987).

    Rabbits

         Mevinphos (purity, 89.6%; 74.5% alpha, 15.1%  isomer) was
    administered in water by gavage to groups of 20 pregnant New Zealand
    white rabbits at doses of 0, 0.05, 0.5, or 1.5 mg/kg bw per day on
    days 7-19 of gestation. Surviving animals were killed on day 29. Body
    weights were measured on days 0 and 7 of gestation, every three days
    until day 25, and on day 29 of gestation. Plasma and erythrocyte
    cholinesterase activity was determined in blood taken from dams about
    3 h after treatment on the last day. After the animals had been
    killed, gross necropsy was carried out, and body weight and the weight
    of the uterus plus ovary were determined. The uterine contents were
    examined, live fetuses were killed, and all fetuses were weighed and
    examined externally. The viscera and skeleton were examined for
    malformations, and half of the fetuses from each litter were examined
    for the presence of brain abnormalities. Brain acetylcholinesterase
    activity was not measured. Maternal toxicity was seen in animals at
    the high dose, resulting in one death; corrected body weights were
    also decreased in that group on day 29 of gestation. Erythrocyte
    acetylcholinesterase activity was statistically significantly reduced
    in all three treated groups. The decreases were not biologically
    significantly in those at the medium and low doses (13% and 6%), but
    the reduction of 18% in animals at the high dose can be considered to
    be marginally biologically significant. Plasma cholinesterase activity
    was more sensitive to mevinphos, being significantly reduced at the
    two higher doses. No significantly different findings among the groups
    were made at autopsy. Mean fetal body weights and the crown-rump
    lengths of the treated pups were similar to those of controls. An
    increased incidence of accessory vessels was seen at 1.5 mg/kg bw
    per day, which was not considered by the authors to be related to
    treatment, as these are normal variations. Hypoplastic hyoids and
    unossified forepaws were also seen at increasing incidence with dose,
    but the difference in incidence between animals at the high dose and
    the controls did not achieve clinical significance. The NOAEL was
    0.5 mg/kg bw per day on the basis of a marginally biologically
    significant decrease in erythrocyte acetylcholinesterase activity in
    animals at the high dose (Beyer, 1991a).

    (f)  Genotoxicity

         Studies on the genotoxicity of mevinphos  in vitro and  in vivo are
    summarized in Table 2.

        Table 4.  Recent tests for the genotoxicity of mevinphos

                                                                                                                                      

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

    In vitro

    Reverse mutation    S. typhimurium TA98,        100-10 000 g/plate      89.6              Negative in TA98     San & Schadly
                        TA100, TA1535,                                       (74.5% alpha,     with and without     (1989)
                        TA1537, TA1538                                       15.1% )          S9
    Sister chromatid    Chinese hamster             10-5-10-3 mol/litre      NR                Positive             Hirka et al.
    exchange            ovary cells                                                                                 (1982)
    Unscheduled DNA     Rat primary hepatocytes     0.0003-0.3 l/ml         NR                Negative             Curren (1990)
    synthesis

    In vivo

    Chromosomal         CF-1 mouse, bone            1.5, 3 mg/kg bw per      70% alpha         Negative             Dean & Senner
    aberration          marrow                      day orally                                                      (1974)
    Dominant lethal     Mouse                       1.5; 3, 6 mg/kg bw       NR                Negative             Dean (1974)
    mutation
                                                                                                                                      

    NR, not reported
        (g)  Special studies

    (i)  Dermal and ocular irritation and dermal sensitization

         Slight dermal irritation and erythema were observed in five of
    six New Zealand white rabbits and oedema in the sixth. Most of the
    effects had disappeared by 72 h. In the same study, the material
    produced slight temporary ocular irritation in six New Zealand white
    rabbits (Deenihan, 1985).

         Groups of five male and five female New Zealand white rabbits
    received applications of mevinphos (74.5% alpha, 15.1%  isomer)
    on the clipped unabraded skin of the back at doses of 0, 0.1, 1,
    or 10 mg/kg bw per day, on five days per week for three weeks.
    The material was not irritating. Males at the highest dose had a
    significant increase in relative brain weight and a decrease in the
    liver:brain and kidney:brain weight ratios. A dose-related decrease in
    brain, erythrocyte, and plasma cholinesterase activity was also seen.
    Plasma, erythrocyte, and brain cholinesterase activities at termination
    were inhibited in males and females at the highest dose by > 15% in
    comparison with concurrent controls. Erythrocyte acetylcholinesterase
    activity was the least inhibited and brain acetylcholinesterase
    activity the most inhibited in animals of each sex. The NOAEL for
    transdermal exposure was thus 1 mg/kg bw per day (Trimmer, 1990b).

         Mevinphos (purity, 93.6%) did not have dermal sensitization
    potential in guinea-pigs (Auletta, 1988c).

    (ii)  Neurotoxicity

    Hens

         Ten Leghorn hens  (Gallus gallus domesticus) were given 12.5 mg/kg
    bw mevinphos (purity, approx. 97%), this dose being slightly greater
    than the oral LD50 for hens. Antidotal treatment was required, and
    0.625 mg/kg bw atropine was given as clinically indicated; each hen
    was also treated with 10 mg/kg bw pralidoxime chloride. Three of the
    treated hens died, despite antidotal therapy; the remainder were
    treated again on day 21 of the study as they had shown no signs of
    neurotoxicity. Four positive controls were treated with tri- ortho-
    tolylphosphate (90% mixture of isomers), but, when no signs of
    neurotoxicity were seen, material from a different supplier was used
    to treat the hens again at 21 days. Hens that survived to 42 days
    were injected with sodium pentobarbital and perfused with neutral
    buffered formalin. Brain, including the medulla, spinal cord, sciatic
    nerve, and the proximal parts of the peroneal and tibial nerves, were
    examined histopathologically. The treated birds had slight weight
    loss, presumably due to the cholinergic effect of mevinphos, but no

    evidence of mevinphos-induced delayed polyneuropathy was seen, either
    clinically or histopathologically, whereas characteristic changes were
    seen in the positive controls. Neuropathy target esterase was not
    measured in this study (Barrett, 1988).

         A single dose of mevinphos (76% alpha, 11%  isomer) was given by
    gavage to groups of 27 male and 27 female Sprague-Dawley Crl:CD BR
    rats at doses of 0, 0.025 (17 rats of each sex), 0.1, 2, or 3.5
    mg/kg bw. Seven animals of each sex per group were allocated for
    neuropathological examination and underwent a functional observation
    battery and tests for locomotor activity before treatment, at the time
    of the peak effect (about 45 min after dosing), and on days 7 and 14.
    These animals were killed at 15 days, and their brains were perfused
     in situ and weighed; neuropathological examination was then carried
    out on five rats of each sex in the control group and those at the
    highest dose. The other 20 animals in each group (10 at 0.025 mg/kg
    bw) were allocated for determinations of cholinesterase activity;
    viability, clinical signs, and body weight were recorded, and the
    functional observation battery and tests for locomotor activity were
    conducted on five rats of each sex per group. Plasma, erythrocyte, and
    brain (including regional) cholinesterase activities were measured
    before treatment, at the time of the peak effect (about 45 min after
    dosing), and on days 7 and 15 in five animals of each sex per group,
    except for those at the lowest dose, in which activity was measured
    only at the time of peak effect and on day 15. The numbers of animals
    available for determination of cholinesterase activity were also
    reduced in the group at the high dose because of mortality (see
    below).

         One male and five females at the highest dose died, and clinical
    signs, including gait alterations, tremors, salivation, and
    lacrimation, were observed in those at 2 or 3.5 mg/kg bw only on the
    day of dosing. Major disturbances in the locomotor test battery
    were observed in animals at these doses but not in controls. The
    alterations included lacrimation, salivation, impaired mobility and
    gait, clonic and tonic convulsions, tremors, bizarre behaviour, and
    altered reflexes. No treatment-related signs were seen in animals
    at 0.025 or 0.1 mg/kg bw. On the first day of the study, plasma
    cholinesterase activity was reduced by 36-39% in rats at 2 mg/kg bw
    and by 41-50% in those at 3.5 mg/kg bw in comparison with concurrent
    controls. Erythrocyte acetylcholinesterase activity was unaffected,
    while reductions of 20-25% were seen in acetylcholinesterase activity
    in the brain stem and/or cerebral cortex, hippocampus, and olfactory
    region of animals at 2 mg/kg bw and 19-36% in those at 3.5 mg/kg bw.
    The only statistically significant reductions in activity were those
    in the brain stem and cortex in males and in the hippocampus and brain
    stem in females. Plasma and brain cholinesterase activities were
    normal on days 7 and 14. No adverse effects were seen on body or brain
    weight. All signs of neurotoxicity had reversed by the end of day 1,

    and no treatment-related neuropathological signs were seen at any
    dose. The NOAEL was thus 0.1 mg/kg bw, on the basis of clinical
    effects and reduced brain acetylcholinesterase activity at higher
    doses (Lamb, 1993).

         Mevinphos was given by gavage in water to groups of 25 male and
    25 female Sprague-Dawley Crl:CD BR rats for 91 days. The initial doses
    for all animals were 0.025, 0.035, or 0.70 mg/kg bw per day, but the
    dose for females at the high dose was reduced to 0.60 mg/kg bw per day
    on day 32 because of the deaths of two animals. Controls received
    the vehicle only. Viability, clinical signs, body weights, and
    food consumption were recorded for all animals, and a functional
    observational battery and locomotor activity tests were conducted on
    10 animals of each sex per group. Necropsy was performed on all
    animals that died during the study. Neuropathological changes were
    evaluated in five animals of each sex in the control group and those
    at the high dose, and, because of the mortality at the high dose, in
    the females at the intermediate dose. The remaining 20 animals in each
    group were evaluated for plasma, erythrocyte, and brain cholinesterase
    activity in groups of five animals during weeks 3, 7, and 12 of the
    study.

         The main clinical sign was tremor in animals at the high dose
    45 min after treatment, even after the dose for the females had been
    lowered. Excessive salivation was seen in animals of each sex at this
    dose, and lacrimation and rles were seen in females. Treatment-
    related declines of 32-56% were seen in erythrocyte and plasma
    cholinesterase activities in animals of each sex at the intermediate
    and high doses; the decreases in erythrocyte acetylcholinesterase
    activity were slightly greater (34-62%). Regional brain acetyl-
    cholinesterase activity showed some variation, with decreases of 9-21%
    in animals at the intermediate and high doses. If decreases of 15% are
    biologically significant, the decreased acetylcholinesterase activity
    of 21% in the mid-brain of males at the middle dose and of 17% in
    females would result in a NOAEL at 0.025 mg/kg bw per day. No
    treatment-related neuropathological change was seen (Lamb, 1994).

         Administration of a single dose of mevinphos (purity, 89.6%)
    to Crl:CD Br rats transdermally did not induce statistically or
    biologically significant depressions in erythrocyte acetyl-
    cholinesterase activity. A significant depression of plasma
    cholinesterase activity occurred at 20 mg/kg bw (29% of control value)
    and a marginal fall at 5 mg/kg bw (11% of control). Significant
    depressions of brain acetylcholinesterase activity occurred at
    20 mg/kg bw (18% of control) (Trimmer, 1989, 1990a).

         The effects of mevinphos on flash-evoked potentials were studied
    in gerbils, pigeons, cats, and squirrel monkeys, through electrodes
    placed in the superior colliculus. Mevinphos reduced the inhibitory
    pause in pigeons at doses of 0.1-0.15 mg/kg bw. This effect could not

    be prevented by pretreatment with atropine methylnitrite (Revzin,
    1978). Electroretinograms of Swiss white mice were examined
    after injection of organophosphates, including mevinphos at an
    intraperitoneal dose of 0.015 mg. Mevinphos was found to interfere
    with retinal function by a direct action on the photoreceptor, by
    inhibition of cholinesterase at synapses, and possibly by damaging the
    bipolar and/or ganglion cells (Carricaburu  et al., 1980).

    3.  Observations in humans

         A number of incidents of poisoning with mevinphos have been
    reported through the US pesticide incident monitoring scheme (Hodgson
    & Smith, 1993). Poisoning with this compound is reported to be
    amenable to treatment with oximes (Bismuth  et al., 1993).

         After administration of 25 g/kg bw per day mevinphos to eight
    male volunteers for 28 days, plasma and erythrocyte cholinesterase
    activity fell throughout the study, with mean decreases of 12.6 and
    19% of the respective pretreatment levels. Plasma cholinesterase
    activity had returned almost to pretreatment levels within seven days
    after the end of treatment, whereas the levels of erythrocyte activity
    showed no sign of recovery at follow-up to 14 days. A decrease in
    slow fibre motor conduction was also seen; there was an increase in
    Achilles tendon reflex force but no effect on neuromuscular
    transmission (Verbeck, 1977; Verbeck & Sall, 1977).

         Mevinphos was given to groups of five male volunteers at doses
    of 1, 1.5, 2, or 2.5 mg per day for 30 days. Plasma cholinesterase
    activity was slightly affected by the highest dose, while the mean
    erythrocyte acetylcholinesterase activity was depressed by 20% on one
    occasion each at 1.5 and 2 mg per day. Consistent, significant
    inhibition of cholinesterase activity was seen only at the highest
    dose, at which the erythrocyte acetylcholinesterase fell consistently
    to a minimum of 25% at 27 days (Rider  et al., 1975).

         In agricultural workers with cholinergic symptoms and with mean
    inhibition of plasma and erythrocyte cholinesterase activity of 15.6
    and 5.6%, respectively, cholinesterase activity recovered at a daily
    rate of 1.2 and 0.43% of the respective final levels of activity of
    the enzyme over the 14 days after cessation of exposure (Coye  et
     al., 1986). Higher rates of recovery were observed during the first
    11 days after poisoning with a mixture of mevinphos and phosphamidon:
    the plasma activity increased by 3% per day and erythrocyte activity
    by 0.8% per day. The workers were, however, treated with pralidoxime.
    As noted previously, inhibition of plasma cholinesterase activity was
    greater than that of erythrocytic enzyme (Midtling  et al., 1985).

         Human erythrocyte acetylcholinesterase is susceptible to
    reactivation  in vitro by a variety of pyridinium oximes, including
    pralidoximes and obidoxime (Woreck  et al., 1996).

    Comments

         Mevinphos is almost completely absorbed when administered orally
    to rats; a large proportion of the absorbed material is biotransformed
    to carbon dioxide. Both metabolites and unchanged mevinphos are
    observed in the urine but very little in the faeces. Mevinphos
    depresses cholinesterase activity in the plasma mre than in the
    erythrocytes in experimental animals.

         The oral LD50 values for mevinphos in laboratory rodents are
    2-12 mg/kg bw. WHO has classified mevinphos as 'extremely hazardous'
    (WHO, 1996).

         In a three-month range-finding study, mice were fed diets
    containing mevinphos at concentrations of 0, 0.5, 1, 2, or 10 ppm.
    The NOAEL was 2 ppm, equal to 0.4 mg/kg bw per day, on the basis of
    inhibition of brain acetylcholinesterase activity at 10 ppm.

         In a 90-day study of toxicity, rats were given mevinphos by
    gavage at doses of 0, 0.056, 0.56, 1.1, or 1.7 mg/kg bw per day were
    used in males (the highest dose was decreased to 1.1 mg/kg bw per day
    at day 36 because of high mortality) and 0, 0.011, 0.056, 0.56, or
    0.84 mg/kg bw per day in females. The NOAEL was 0.056 mg/kg bw per
    day, on the basis of clinical signs and depressed brain acetyl-
    cholinesterase activity at higher doses. Dose-related increases in
    mean cholesterol levels and increased relative liver weights were also
    observed.

         In a one-year study in dogs, mevinphos was administered in corn
    oil in gelatine capsules at doses of 0, 0.025, 0.25 or 0.5 mg/kg bw
    per day. The NOAEL was 0.25 mg/kg bw per day on the basis of clinical
    signs and a reduction in brain acetylcholinesterase activity at the
    highest dose.

         In an 18-month study of toxicity and carcinogenicity, mice were
    fed dietary concentrations of 0, 1, 10, or 25 ppm; cholinesterase
    activity was not measured. There was no evidence of carcinogenicity.

         In a two-year study of toxicity and carcinogenicity, rats were
    given mevinphos by gavage in water on five days per week at doses of
    0, 0.025, 0.35, or 0.70 mg/kg bw per day. On day 83 of the study, the
    high dose of the females was reduced to 0.60 mg/kg bw per day because
    of signs of toxicity. The NOAEL was 0.025 mg/kg bw per day on the
    basis of inhibition of brain acetylcholinesterase activity and clinical
    signs at higher doses. There was no evidence of carcinogenicity.

         A two-generation study of reproductive toxicity was carried out
    in which rats were treated by gavage at doses of 0, 0.05, 0.1, or
    0.5 mg/kg bw mevinphos in water. The NOAEL was 0.1 mg/kg bw per day on
    the basis of clinical signs and reduced brain acetylcholinesterase
    activity at the highest dose. This dose also impaired growth and
    fertility indices and lowered testicular weights in males and ovarian
    weights in females.

         In a study of developmental toxicity in rats, groups were given
    mevinphos at daily doses of 0, 0.2, 0.75, or 1.2 mg/kg bw per day on
    days 6-15 of gestation. High mortality (29%) was observed in the
    high-dose group, which was therefore terminated; accordingly, a new
    high-dose group at 1 mg/kg bw per day was added. There were no adverse
    effects on uterine implantation or on fetal weight, sex distribution,
    external appearance, or visceral or skeletal malformations in any
    group. It was concluded that mevinphos is not embryotoxic, fetotoxic,
    or teratogenic at doses < 1.0 mg/kg bw per day. The NOAEL for
    maternal toxicity was 0.75 mg/kg bw per day on the basis of clinical
    signs at higher doses.

         In a study of developmental toxicity, mevinphos was administered
    by gavage to pregnant rabbits at doses of 0, 0.05, 0.5, or 1.5 mg/kg
    bw per day on days 7-19 of gestation; surviving animals were killed.
    The NOAEL was 0.5 mg/kg bw per day, on the basis of maternal toxicity.
    Mevinphos was neither teratogenic nor fetotoxic.

         There was some evidence of genotoxic potential  in vitro, but
    the limited studies available indicate that such potential is not
    exhibited  in vivo.

         In a study in hens, the oral dose of 12 mg/kg bw that was
    administered was slightly greater than the oral LD50 value, and
    antidotal treatment was required. There was no evidence of delayed
    polyneuropathy, either clinically or histopathologically, whereas
    characteristic changes were seen in positive controls. Neurotoxic
    target esterase was not measured during this study.

         Two studies of humans were available. In male volunteers given a
    dose of 0.025 mg/kg bw per day, plasma and erythrocyte cholinesterase
    activity decreased throughout the 28 days of the study to 13% and 19%
    less than the respective pre-dose levels. In the second study, daily
    doses of 1, 1.5, 2 or 2.5 mg were given to male volunteers for 30
    days, and an NOAEL of 1 mg/day, equivalent to 0.016 mg/kg bw per day,
    was derived; however, only five people, all men, per dose were
    studied.

         An ADI of 0-0.0008 mg/kg bw was established on the basis of the
    NOAEL of 0.016 mg/kg bw per day in the 30-day study in volunteers,
    using a 20-fold safety factor because of the small numbers in each
    group. This ADI is supported by the LOAEL in rats of 0.35 mg/kg bw per
    day and the NOAELs of 0.5 mg/kg bw per day in rabbits and 0.25 mg/kg
    bw per day in dogs.

         An acute reference dose for humans was derived from the 28-day
    study in volunteers, on the basis of a dose of 0.025 mg/kg bw per day,
    using a 10-fold safety factor.

    Toxicological evaluation

    Levels that cause no toxicological effect

         Mouse:    2 ppm, equal to 0.4 mg/kg bw per day (inhibition of
                   brain acetylcholinesterase activity in a three-month
                   study of toxicity)

         Rat:      0.025 mg/kg bw per day (two-year study of toxicity and
                   carcinogenicity)

                   0.1 mg/kg bw per day (study of reproductive toxicity)

         Rabbit:   0.5 mg/kg bw per day (maternal toxicity in a study of
                   developmental toxicity)

         Dog:      0.25 mg/kg bw per day (one-year study of toxicity)

         Human:    1 mg per day, equivalent to 0.016 mg/kg bw per day
                   (inhibition of cholinesterase activity in a 30-day
                   study of toxicity)

    Estimate of acceptable daily intake for humans

         0-0.0008 mg/kg bw

    Acute reference dose

         0.003 mg/kg bw

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

         Study of micronucleus formation in mice  in vivo

        Toxicological criteria for estimating guidance values for dietary and non-dietary exposure to mevinphos

                                                                                                                                      

           Exposure                  Relevant route, study type, species                         Results, remarks
                                                                                                                                      

    Short-term (1-7 days)        Oral, toxicity, rat                              LD50 = 2.2-6.1 mg/kg bw
                                 Dermal, toxicity, rat                            LD50 > 20 mg/kg bw
                                 Inhalation, 4 h, toxicity, rat                   LD50 = 7.3-12 mg/m3
                                 Dermal, irritation, rabbit                       Slightly irritating
                                 Ocular, irritation, rabbit                       Slightly irritating
                                 Dermal, sensitization, guinea-pig                Not sensitizing

    Medium-term (1-26 weeks)     Repeated oral, 3 months, mouse                   NOAEL = 0.4 mg/kg bw per day, inhibition of brain
                                                                                  acetylcholinesterase activity
                                 Repeated oral, 90 days, rat                      NOAEL = 0.056 mg/kg bw per day
                                 Repeated dermal, 21 days, rabbit                 NOAEL = 1.0 mg/kg bw per day
                                 Repeated oral, reproductive toxicity, rat        NOAEL = 0.1 mg/kg bw per day, maternal and
                                                                                  reproductive toxicity
                                 Repeated oral, developmental toxicity, rat       NOAEL = 0.75 mg/kg bw per day, maternal toxicity;
                                                                                  no developmental toxicity
                                 Repeated oral, developmental toxicity, rabbit    NOAEL = 0.5 mg/kg bw per day, maternal toxicity;
                                                                                  no developmental toxicity

    Long-term (> 1 year)         Repeated oral, 2 years, rat                      NOAEL = 0.025 mg/kg bw per day; inhibition of
                                                                                  brain acetylcholinesterase activity
                                 Repeated oral, 1 year, dog                       NOAEL = 0.25 mg/kg bw per day; inhibition of
                                                                                  brain acetylcholinesterase activity
                                                                                                                                      
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    See Also:
       Toxicological Abbreviations
       Mevinphos (FAO Meeting Report PL/1965/10/1)
       Mevinphos (WHO Pesticide Residues Series 2)
       Mevinphos (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)