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    DICHLORVOS     JMPR 1977

    Explanation

    This pesticide was evaluated by the 1965, 1966, 1967, 1970 and 1974
    Joint Meetings (FAO/WHO, 1965, 1967, 1968, 1971, 1975). Since the
    previous evaluation additional data have become available and are
    summarized and discussed in the following monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, distribution and excretion

    Dichlorvos is rapidly absorbed, distributed and excreted in mammals.
    Studies utilizing 32P-labelled dichlorvos have been previously
    discussed (FAO/WHO 1967; FAO/WHO, 1971). Additional biochemical
    studies utilizing methyl-14C, vinyl-14C, 3H and 36Cl-labelled
    dichlorvos have become available since these previous evaluations.

    Three male rats were given a single oral dose of 0.99 mg of
    vinyl-1-14C dichlorvos in oil to determine the metabolism, excretion
    and distribution of the vinyl moiety of dichlorvos. Similarly, three
    female rats were treated with 0.72 mg of vinyl-1-14C dichlorvos. In
    both sexes, over a 4 day period approximately 40% of the administered
    radioactivity was expired as CO2, 10-20% was excreted in the urine
    and 3-5% in the faeces. Of the retained radioactivity, approximately
    5% was found in the liver, 2% in the gut, 8% in the skin and 14% in
    the carcass. In this same report similar results were found when three
    male rats were exposed to similar dose levels of vinyl-l-14C
    dichlorvos vapour for one hour. In contrast, the intraperitoneal
    injection of 0.6 mg of vinyl-1-14C dichlorvos two male rats resulted
    in less of the administered radioactivity being expired as CO2 (19%)
    and a higher level of excretion in the urine (35%) and retention in
    the carcass (23%) (Huston et al., 1971).

    Intramuscular injection of a female rat with a single 19 mg dose of
    36 Cl-labelled dichlorvos in the right groin, after atropine and
    obidoxime injection into the left groin, resulted in a 64% excretion
    of radioactivity in the urine during the first 9 days (Hutson et al.,
    1971).

    To study the metabolism, distribution and excretion of the methyl
    groups of dichlorvos rats were given a single oral dose of
    approximately .35 mg/kg 14C-methyl-labelled dichlorvos. During the
    next four days, approximately 60% of the administered radioactivity
    was excreted in the urine, 5% in the faeces and 15% as expired CO2.
    The carcass, skin and gut contained approximately 5, 2 and 1% of the
    administered radioactivity respectively. No differences were observed
    between the sexes. In male and female mice receiving a single oral
    dose of approximately 2 mg/kg a similar excretion and residue pattern
    was observed (Hutson and Hoadley, 1972).

    Three male pigs were fed 40 mg/kg vinyl-1-14C dichlorvos encapsulated
    in polyvinyl chloride pellets. After 14 days approximately 60% of the
    administered radioactivity was recovered in the encapsulated pellets
    in the faeces. The expired CO2 accounted for approximately 15% of the
    administered dose, 5% was excreted via the urine, 5% via the faeces
    and the carcass contained approximately 10% of the administered dose.
    Of 20 tissues examined, the highest level of radioactivity was found
    in liver tissue and the lowest in brain tissue (Potter et al., 1973a).

    Pregnant sows were given multiple 4 mg/kg doses of vinyl-14C or
    36Cl-labelled dichlorvos in polyvinyl chloride pellets. In this
    experiment less of the administered 14C radioactivity was expired as
    CO2 and more was released from the polyvinyl chloride pellets than in
    the feeding study with male pigs described above.

    Dichlorvos-36Cl recoveries from the sows comprised approximately 60%
    recovered in pellets in the faeces, 6% in faeces, 25% in urine and 8%
    in the carcass. In the newborn piglets, 14C tissue residues were
    increased in the femur, as were 36Cl residues. This increase is
    apparent up to sacrifice at 21 days of age. Heart 36Cl residues (no
    data on 14C) were also elevated. By 21 days, 14C residues were
    reduced for kidney, liver, lungs, muscle, spleen and stomach as
    compared with residues in the sow. 36Cl residues are reduced at birth
    and up to 21 days, as compared with the sow, in the kidney, liver,
    lungs, muscle, salivary gland, spleen and stomach. The 36Cl residues
    in the piglets are maximal for all tissues at 9 days of age (Potter et
    al., 1973b).

    Pigs were exposed for 24 days to an atmosphere of vinyl-1-14C
    dichlorvos (0.1-0.15 g/). Twice as much 14C was excreted in the
    urine as in the faeces, (Loeffler et al., 1976).

    Rats and mice were treated with unlabelled dichlorvos to study the
    distribution in tissues by inhalation or intravenous administration.
    No dichlorvos was detected in the blood, liver, kidney, renal fat or
    lung tissues of rats exposed to 0.5 or 0.05 g/1 for 14 days: the
    kidney, trachea and fat tissue from male rats exposed to 90 g/1
    contained detectable quantities. In female rats treated similarly the
    trachea, fat, blood and brain tissue contained detectable quantities
    of dichlorvos. Intravenous administration of 0.25 mg dichlorvos/rat in
    males and females with autopsies 10 and 30 mins. after dosing,
    indicates rapid destruction of dichlorvos, based on kidney residues in
    the male. In females, dichlorvos was not detectable in the kidney
    (Blair et al., 1975).

    Biotransformation

    The metabolic fate of dichlorvos in rats, mice and swine following
    oral ingestion, inhalation exposure, or intraperitoneal injection were
    similar. Biotransformations occurred primarily as a result of
    hydrolytic, oxidative or demethylating enzymes which detoxified the
    parent compound.

    Analysis of the urine of rats orally dosed with vinyl-1-14C labelled
    dichlorvos indicated that the major urinary metabolites are hippuric
    acid (8%), 2,2-dichlor-vinyl-methyl-phosphate (11%), dichloroethanol
    glucuronide (27%) and urea (3.1%). Three other unidentified
    metabolites were noted. No unchanged dichlorvos was detected in the
    urine. Inhalation exposure resulted in a similar pattern of
    metabolites in the urine. Intraperitoneal administration resulted in
    dichloroethanol glucuronide as the major urinary metabolite (76%) and
    small amounts of hippuric acid and 2,2-dichlorovinyl methyl phosphate
    (Hutson et al., 1971).

    When 14C-methyl-labelled dichlorvos was administered orally to rats
    and mice the major urinary metabolites were dimethyl phosphate (77% in
    rats, 64% in mice) and 2,2-dichlorovinyl methyl phosphate (3.5% in
    rats, 25% in mice). Minor metabolites were S-methyl-L-cysteine oxide,
    S-methyl-L-cysteine and methylmercapturic acid (Hutson and Hoadley,
    1972).

    When pigs were treated orally with 14C-methyl-labelled dichlorvos in
    a slow release polyvinyl chloride pellet, no dichlorvos,
    2,2-dichlorovinyl phosphate, dichloroacetaldehyde or dichloroacetic
    acid was detected in any tissue samples (Potter et al., 1973a).

    When pigs were exposed to 1-vinyl-14C-labelled dichlorvos by
    inhalation (0.1-0.15 g/1), the major metabolites identified were
    glycine, serine and adenine (Loeffler et al., 1976).

    Pregnant sows were treated with 4 mg/kg of 14C-methyl-or
    36Cl-labelled dichlorvos orally in a slow release polyvinyl chloride
    pellet. No dichlorvos, dichloroacetaldehyde, 2,2-
    dichlorovinylmethyl-phosphate, dichloracetic acid or dichloroethanol
    was found in the tissues. (Potter et al., 1973b).

    Other Biochemical Parameters

    Several studies have been carried out to determine the potential for
    direct methylation of nucleic acids by dichlorvos.

    C14-methyl-dichlorvos was found to be a weak methylating agent in DNA
    pre-isolated from E. coli and Salmon sperm. The principal products
    were 7-methylguanine, 3-methyladenine, 3-methylguanine and trace
    levels of other methylated bases. Methylation was also found when
    14C-methyl dichlorvos was incubated with intact cells of E. coli
    and the HeLa tumour line. However, the principal product was
    7-methylguanine and no 3-methylguanine was found in these cells
    (Lawley et al., 1974).

    E. coli cells were incubated with methyl-14C-dichlorvos to study
    the methylation of DNA and RNA. 14C-labelled 7-methylguanine was
    found in DNA and RNA isolated from treated cells (Wennerberg and
    Lofroth, 1974).

    Mice were exposed to 14C-methyl dichlorvos by inhalation or i.p.
    injection. Analysis of the urine collected from two successive 24 hour
    periods from these mice showed the excretion of 14C-labelled
    7-methylguanine (Wennerberg and Lofroth, 1974).

    Mice and rats were exposed to methyl-14C-labelled dichlorvos by
    inhalation or i.p. injection. Analysis of the hydrolysate from the
    mouse liver protein showed incorporation of 14C activity into amino
    acids. Labelled 7-methylguanine, 3-methyl adenine and
    1-methylnicotinamide was found in the urine of treated rats. 14C
    labelled guanine and adenine were found in the DNA and RNA from liver
    and lung tissues of treated mice. However, no detectable amount of
    7-methylguanine was found in the DNA or RNA from lung or liver tissues
    (Wennerberg, 1973).

    Rats were exposed to an atmosphere containing 0.064 g/1 of
    methyl-14C-labelled dichlorvos for 12 hours to study the methylation
    of DNA and RNA in vivo. Traces of radioactivity were found in the
    DNA, RNA and protein fractions from brain, heart, lung, liver, spleen,
    kidney and testes. The 14C activity was not associated with any
    UV-absorbing component. The 7-methylguanine fraction from the pooled
    tissue samples was assayed for 14C activity by 20 repeated 7 hour
    counts. No significant difference was detected between the test and a
    blank 7-methylguanine fraction. The purine fraction of the urine from
    treated rats contained no detectable 14C as 7-methylguanine (Wooder
    et al., 1977).

    Special studies on mutagenicity

    Two review papers on the alkylating and mutagenic properties of
    dichlorvos in microorganisms, drosophila, tissue culture, host
    mediated assays and humans were submitted for consideration.
    Conclusions drawn in both papers are essentially the same. Under
    conditions of normal use as an insecticide, dichlorvos cannot exert
    significant mutagenic effects in mammals, including humans. This view
    is based mainly on the mutagenicity for microbes, the DNA alkylating
    property of dichlorvos at high concentrations and the results from
    analytical determinations in issues of treated mammals. Tissue
    concentrations in mammals are lower than 10-3 to 10-5 times the
    lowest concentrations mutagenic for microbes in vitro (Wild, 1975).
    Various types of study performed with dichlorvos in in vivo host
    mediated assay, dominant lethals assays, bone marrow cytogenetic
    analysis and chromosome analysis of spermatocytes in mice treated by
    inhalation have all been negative. On the basis of these results
    dichlorvos does not represent a mutagenic risk for humans domestic
    doses (Loprieno, undated).

    Special studies on carcinogenicity

    Mice

    Two groups of 50 male and 50 female mice (age not specified) were fed
    1000 and 2000 ppm 94% minimum purity dichlorvos in the diet for 2
    weeks. Because of severe signs of toxicity, levels were reduced to 300
    and 600 ppm for the remaining 78 weeks of administration. Mice were
    autopsied 12-14 weeks after cessation of dosing. Matched controls
    comprised 10 mice/sex maintained for 92 weeks. The minimum survival
    (low dose females) was 74% at 90 weeks. Average weights of high dose
    level mice were slightly depressed. Analysis of tumours at autopsy did
    not reveal any compound- or dose-related effects (Anon, 1977).

    Rats

    Two groups of 50 male and 50 female rats were run 4 weeks apart. Group
    1 consisted of rats 43 days of age, which were fed 1000 ppm in the
    diet for 3 weeks, which because of signs of toxicity was reduced to
    300 ppm for the subsequent 77 weeks of administration. Autopsy was
    performed 30-31 weeks after cessation of dosing. Five rats/sex were
    maintained for 110 weeks as controls. Group 2 consisted of 36 day old
    rats which were fed 150 ppm in the diet for 80 weeks, with autopsy 30
    weeks after cessation of dosing. Again controls comprised 5 rats/sex
    maintained for 110 weeks. Body weights of high dose rats were
    constantly reduced. Analysis of tumours at autopsy did not reveal any
    compound- or dose-related effects (Anon, 1977).

    Four groups of 50 male and 50 female rats were exposed to nominal air
    concentrations of 0, 0.05, 0.5 or 5 mg dichlorvos/m3 air for 23
    hours/day for 2 years. (Groups of 10 M and 10 F/dose level commenced
    exposure each week for 5 weeks. Average actual dichlorvos
    concentrations were 0.05, 0.48 and 4.70 mg/m3. Necropsies were
    performed on all rats dying naturally, or killed at termination of the
    study. Data on tumour incidence was analyzed using actuarial analysis,
    comparing observed with expected tumour incidence, and then performing
    a risk assessment. No gross pathological changes were noted which were
    related to dichlorvos exposure. Microscopic examination of animals
    dying in the study was frequently difficult, owing to autolysis
    resulting from inability to examine animals more than once daily,
    without upsetting the vapour exposure requirements. Tumour incidence
    data were therefore analyzed with respect to all rats in the study and
    also with respect to those dead animals where microscopic examination
    was possible in detail. Results indicated a higher incidence of
    tumours in the latter group. Thus, considering all rats, percentage
    occurrence of tumours in males was 36, 60, 52 and 48% and in females
    77, 60, 77 and 72% at 0, 0.05, 0.5 and 5.0 mg/m3. The breakdown of
    these data indicate that 31, 48, 49 and 43% of male rats dying during
    the experiment had tumours at 0, 0.05, 0.5 and, 5 mg/m3.
    Corresponding figures for females are 68, 60, 57 and 67%, for males
    surviving until termination 55, 76, 60 and 56%, and for females 86,
    59, 92 and 74% (Blair at al., 1976).

    Short term studies

    In a study of the anthelmintic efficacy of dichlorvos for schislosome
    and filarial infections, 32 rhesus monkeys, sex undisclosed, were
    treated with pelleted polyvinyl chloride resin formulations of
    dichlorvos at dosages ranging from 5 to 80 mg/kg daily or 8 and 20
    mg/kg twice daily for 10 to 21 consecutive days. None of the monkeys
    developed clinical signs which could be attributed to treatment.
    Plasma and erythrocyte cholinesterase activities were significantly
    inhibited in all animals (Hass at al., 1972).

    Long term studies

    Groups of rats (50/sex/group) were exposed to 97% technical dichlorvos
    at nominal concentrations of 0, 0.05, 0.5 and 5.0 mg/m3 of air for 2
    years. The details of experimental design are given in the second rat
    study in "Special studies on carcinogenicity".

    No signs of organophosphorus toxicity nor consistent differences in
    food intake were seen in any group. In 3 female rats/group, brain
    tissue examined for acethylcholine and choline revealed no
    compound-related effects. Cholinesterase activity in plasma and brain
    was significantly reduced in both sexes exposed to 0.5 and 5.0 mg/m3.
    Erythrocyte activity was significantly reduced in both sexes at 5.0
    mg/m3 but only in females at 0.5 mg/m3. Enzyme activity in males
    exposed to 0.05 mg/m3 was not significantly different from that of
    controls. Female erythrocyte activity was significantly different at
    this level but plasma and brain cholinesterase values were not. Body
    weights of both series of the 5.0 mg/m3 group were significantly
    depressed for the major portion of the study as they were for the 0.5
    mg/m3 males. There were no compound-related effects on organ body
    weight ratios or haematological or blood chemistry values except for
    some increase in PGPT and PGOT activities and a decrease in plasma
    chloride concentration in males exposed to 5.0 mg/m3.

    Minor lesions of the respiratory tract did not correlate with exposure
    levels. Ultra-structural examination of bronchi and alveoli of small
    numbers of 0 and 5 mg/m3 rats showed no differences between groups.
    Necropsies revealed no gross microscopic tissue damage related to
    compound effect in the respiratory tract or elsewhere and no increased
    incidence of tumours was found (Blair et al., 1976).

    OBSERVATIONS IN HUMANS

    No new data were submitted.

    COMMENTS

    On the basis of recent and earlier studies, the metabolic patterns of
    dichlorvos in animals are clearly elucidated. It is rapidly broken
    down in mammals to products which are excreted or incorporated into
    natural biosynthetic pathways.

    Several new studies have examined the potential for direct methylation
    of nucleic acids by dichlorvos. It has been shown to cause the
    methylation of bacterial and mammalian DNA and RNA in vitro. Also
    the urine from dichlorvos-treated mice and rats was found to contain
    methylated purines. The alkylating properties of dichlorvos led to the
    suspicion that dichlorvos might be mutagenic and/or carcinogenic.
    However, no methylated 7-methyl-guanine has been detected in the DNA
    or RNA from liver or kidney tissue or other soft tissues of rats or
    mice treated with 14C-methyl-labelled dichlorvos.

    Although dichlorvos is a potential alkylating agent of DNA and RNA
    in vitro, this potential is apparently not realized in vivo owing
    to the rapid degradation of dichlorvos in mammals. The presence of
    14C-labelled purines in the urine of animals treated with 14C-
    labelled methylating agents is not conclusive proof of the methylation
    of DNA and RNA at the polymeric level. The 14C may be incorporated
    into the free purine bases. Thus, animals treated with 14C-labelled
    guanine excreted 14C-labelled 7-mehtylguanine in the urine.

    These studies and the negative results in mammalian mutagenicity and
    carcinogenicity studies support the view that dichlorvos has an
    extremely low potential for producing mutations or cancer in humans.
    None of the recent studies have changed the basis for establishing an
    ADI.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

        Humans: 0.033 (mg/kg bw)/day

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR

        0-0.004 mg/kg bw

    REFERENCES

    Anonymous, (1977) Bioassay of dichlorvos for possible carcinogenicity.
    Unpublished report from National Cancer Institute, submitted by Shell
    Chemical Co., USA.

    Blair, D., Hoadley, E.C. and Hutson, D.H., (1975) The Distribution of
    Dichlorvos in the tissues of mammals after its inhalation or
    intravenous administration. Toxicology and Applied Pharmacology, 31,
    243-253.

    Blair D., Dix, K.M., Hunt, P.F., Thorpe, E., Stevenson, D.E. and
    Walker, A.I.T. (1976) Dichlorvos -- A 2 year inhalation carcinogensis
    study in rats. Arch Toxicol. 35, 281-294.

    FAO/WHO, (1967) Evaluation of some pesticide residues in food. FAO PL:
    CP/15; WHO/Food Add/67.32

    FAO/WHO, (1971) 1970 Evaluation of some pesticides residues in Food
    AGP: 1970/M/12/1. WHO/Food Add./71.42

    Hass, D.K., Collins, J.A. and Kodama, J.K. (1972) Effects of orally
    administered dichlorvos in Rhesus monkeys. J. Amer. Vet. Med. 161
    (6) 714-719.

    Hutson, D.H. Hoadley, E.C. and Pickering, B.A. The Metabolic Fate of
    (Vinyl-1-14C) Dichlorvos in the rat after oral and inhalation
    exposure. Xenobotica, Vol. 1, No. 6, 593-611.

    Hutson, D.H. and Hoadley, E.C. (1972) The Metabolism of (14C-Methyl)
    dichlorvos in the rat and mouse. Xenobotica, Vol. 2, No. 2, 107-116.

    Hutson, D.H. (1976) The metabolic rate of DDVP in mammals. Unpublished
    Report from Shell Toxicology Laboratory (Tunstall) submitted to the
    World Health organization by Shell Chemical Company.

    Loprieno, M. (no date) Mutagenic properties of dichlorvos: A short
    review. Unpublished review submitted to the World Health Organization
    by Shell Chemical Company.

    Lawley, P.D., Shah, S.A. and Orr, D.J. (1974) Methylation of nucleic
    acids by 2,2-Dichlorovinyl dimethyl Phosphate (Dichlorvos, DDVP)
    Chem-Biol. Interations, 8 171-182.

    Loeffler, J.E., Potter, J.C., Scordelis, S.L., Hendrickson, H.R.,
    Hutson, C.K. and Page, A.C. (1976) Long term exposure of swine to a
    (14C) dichlorvos atmosphere. J. Agric. Food Chem., 24, No. 2,
    163-166.

    Potter, J.C., Boyer, A.C., Marxmiller, R.L., Young, R. and Loeffler,
    J.E. (1973b) Radioisotope Residues and Residues of Dichlorvos and its
    metabolites in pregnant sows and their progeny dosed with
    dichlorvos-14C or dichlorvos-36Cl. Formulated as PVC pellets.
    Jour. Agric. Food 21, No. 4, 734-738.

    Wennerberg, R. (1973) The methylation products after treatment with
    dichlorvos and dimethyl sulfate in vitro. Unpublished thesis from
    Biological Radiation Institute submitted to the World Health
    Organization by Shell Chemical Company.

    Wennerberg, R. and Lofroth, S. (1974) Formation of 7-methylguanine by
    dichlorvos in bacteria and mice. Chem-Biol. Interactions, 8,
    339-343.

    Wild D. (1975) Mutagenicity studies on organophosphorus insecticides.
    Mutation Research, 32, 133-150.

    Wooder, M.F., Wright, A.S. and King, L.P. (1977) In vivo alkylation
    studies with dichlorvos at practical use concentrations. Unpublished
    report from Tunstall Laboratory submitted to the World Health
    Organization by Shell Chemical Company.

    FAO/WHO (1965) Evaluation of the toxicity of pesticide residues in
    food. FAO Meeting Report, No. PL:1965/10/1; WHO/Food Add/27.65.

    FAO/WHO (1968) 1976 evaluation of some pesticide residues in food.
    FAO/PL:1967/M/11/1; WHO/Food Add./68.30.

    FAO/WHO (1975) 1974 evaluations of some pesticide residues in food.
    AGP:1974/M/11; WHO Pesticide Residues Series, No. 4.
    


    See Also:
       Toxicological Abbreviations
       Dichlorvos (EHC 79, 1988)
       Dichlorvos (HSG 18, 1988)
       Dichlorvos (ICSC)
       Dichlorvos (FAO Meeting Report PL/1965/10/1)
       Dichlorvos (FAO/PL:CP/15)
       Dichlorvos (FAO/PL:1967/M/11/1)
       Dichlorvos (FAO/PL:1969/M/17/1)
       Dichlorvos (AGP:1970/M/12/1)
       Dichlorvos (WHO Pesticide Residues Series 4)
       Dichlorvos (Pesticide residues in food: 1993 evaluations Part II Toxicology)
       Dichlorvos (IARC Summary & Evaluation, Volume 53, 1991)