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    PESTICIDE RESIDUES IN FOOD - 1982


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1982





    Data and recommendations of the joint meeting
    of the FAO Panel of Experts on Pesticide Residues
    in Food and the Environment and the
    WHO Expert Group on Pesticide Residues
    Rome, 23 November - 2 December 1982

    Food and Agriculture Organization of the United Nations
    Rome 1983


    PHORATE

    C2H5O  S
         \ "
           P - S - CH2SC2H5
         /
    C2H5O

    Explanation

         This compound was evaluated by the 1977 (FAO/WHO 1978)1 Joint
    Meeting, but no ADI was allocated primarily due to the absence of
    long-term studies. Further studies were required by the previous
    Meeting to evaluate carcinogenic potential, teratogenic potential,
    potential neurotoxicity and toxicity of metabolites. Observations in
    humans were considered desirable. Some of the required studies have
    been submitted and are reviewed in this monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    TOXICOLOGICAL STUDIES

    Special Study on Teratogenicity

    Rat

         Groups of 25 mated female rats (CRL:COBS CD (SD)BR) were
    intubated with technical phorate (purity not given) at 0, 0.125, 0.25
    or 0.5 mg/kg bw/day on gestation days 6 through 15 (day 0 = day
    copulatory plug present). The dams were sacrificed on day 20 of
    gestation and the foetuses were removed for gross, skeletal and
    visceral examination. Pregnancy rate was comparable in all groups.
    During the gestation period, 7/23 and 1/24 pregnant dams,
    respectively, at 0.5 mg/kg bw/day and 0.125 mg/kg bw/day died. An
    increased frequency of foetuses at 0.5 mg/kg bw/day was found to have
    enlarged heart. Other parameters evaluated, i.e. clinical signs, body
    weight and food consumption of dams during gestation, number of
    implantation sites, number of resorptions, number of dead foetuses,
    mean live litter size, average foetal weight, sex ratio, gross,
    skeletal and visceral abnormalities of foetuses, were not
    significantly different from those in the controls. The teratogenic
    "no effect" appeared to be 0.25 mg/kg bw (Litton 1978).

         Groups of pregnant Sprague-Dawley rats (15 controls and 10
    animals/treated group) were exposed (nose-only) in an inhalation 

              

    1  See Annex 2 for WHO and FAO documentation.

    chamber to aerosols (with a count median diameter of 0.57 Ám) of
    technical phorate (78-90% pure) generated from a 1% solution of
    phorate in xylene 1 hour/day from day 7 through 14 of gestation at
    concentrations of 0.15 ▒ 0.04, 0.4 ▒ 0.15 or 1.94 ▒ 0.48 mg/m3. Three
    groups of dams were used, respectively, as xylene controls, air
    controls and restricted food controls. (The reason for including the
    last group in the study was not specified.) All dams were sacrificed
    on the 20th day of gestation and foetuses were removed by caesarean
    section for visceral and skeletal examination. Five dams at the top
    dosage group died and toxic signs (tremors, lacrimation and
    exophthalmus) were noted in animals of this level. The entire litter
    was resorbed in one of the dead dams. Based on summary data available,
    there appeared to be no compound-related effects on body weight and
    food consumption of dams during gestation, pregnancy rate, average
    number of implants, average foetal weight, average number of sternal
    ossification centres and incidence of supernumerary ribs. Average
    foetal mortality (%) was markedly increased in the top dosage level.
    No specific information was available on the incidence of any gross or
    soft tissue abnormalities observed (Newell and Dilley 1978).

    Special Studies on Carcinogenicity

         (See also under Long-Term Studies).

    Mouse

         Groups of 41-day old mice (CD-1 strain, outbreed Swiss Albino, 50
    males and 50 females/group) were fed technical phorate (85.5% pure) in
    their diet at 0, 1, 3 or 6 ppm for 18 months. All animals dying or
    sacrificed in moribund condition during the study or sacrificed
    terminally, were subjected to gross and histopathological examination.
    Survival was not adversely affected with 78-90% males and 66-74%
    females of control and treated groups being still alive terminally.
    Growth retardation was seen in females at 6 ppm practically throughout
    the experiment. Animals of all treated groups appeared to consume less
    food during the first 3 weeks and occasionally thereafter, but a
    consistent dose-response relationship was not evident. Some clinical
    signs, such as tremors, hyperactivity and excessive salivation, seemed
    to occur at higher incidence and more frequently in animals of top
    dosage group than in controls. Gross pathological findings were not
    significantly different from those in the controls. Microscopic
    evaluation of a wide range of tissues from each animal revealed no
    alterations related to inclusion of phorate in the diet. Analysis of
    tumour data indicated no significant dose-related increase in
    incidence of any particular type of tumours, animals with tumours,
    animals with malignant tumours and animals with multiple primary
    tumours. Although incidence of alveolar/bronchiolar adenoma appeared
    to be increased in males at 6 ppm (8/50 vs 3/50 controls) this was not
    believed to be treatment-related since the increase was not
    statistically significant, and the particular tumour is known to occur

    frequently in control CD-1 mice. Under the conditions of the
    experiment, phorate was not carcinogenic in the mouse (Litton 1981a).

    Acute Toxicity

         The acute toxicity of phorate in the rat is summarized in Table 1
    and of phorate and its metabolite in the rat and mouse in Table 2.

    Table 1.  Acute Toxicity of Technical Phorate in Adult
              Sprague-Dawley Rats 1
                                                                        

    Route               Sex       LD50 (mg/kg bw) or LC50 (mg/m3)
                                                                        

    Oral                M                       3.7
                        F                       1.4

    Intravenous         M                       2.2
                        F                       1.2

    Dermal              M                       9.3
                        F                       3.9

    Inhalation          M                      60
    (1-hour exposure)   F                      11
                                                                        

    1  Vehicle of administration was propylene glycol for the oral,
    intravenous and dermal studies. The aerosols were generated from a 1%
    solution of phorate in xylene. Duration of dermal exposure was not
    specified, Source: Newell and Dilley 1978.

    Table 2.  Acute Toxicity of Phorate and Metabolites of Phorate 1
                                                                        

                                     LD50 (mg/kg body weight)
    Compound                        Rat                   Mouse
                             Oral        Dermal       Oral      i.p.
                                                                        

    Phorate                  1.9-10         3           11      3
    Phorate sulphoxide       2 - 4         11            7      1
    Phorate sulphone         1.8-2         27            9      2
    Phoratoxon               0.6-0.8
    Phoratoxon sulphoxide    1.4-1.6        1            3      0.02
    Phoratoxon sulphone      0.6-0.8        1.8          5      0.4
                                                                        
    1  No information was available on strain and sex of animals or
    other details of the studies such as vehicle of administration,
    duration of dermal exposure, etc. Source; Blinn 1982.

    Short-Term Studies

    Rat

         Groups of rats (Charles River CD strain, 51 days of age, 50 males
    and 50 female controls, 30 male and 30 females /treated group) were
    fed phorate sulphone (92% pure also containing 6% unchanged phorate
    and about 2% of the sulphoxide derivative) in their diet at 0, 0.32,
    0.8 or 2 ppm for 90 days. No mortality occurred. There were no
    compound-related changes in appearance and behavior. Weight gain
    appeared to be increased in males at both 0.8 and 2 ppm, together with
    an increase in food consumption. Assay of tissue cholinesterase five
    times over the course of the experiment indicated inhibition (20%) of
    erythrocyte cholinesterase at 2 ppm (both sexes) at most time
    intervals. Plasma cholinesterase was reduced at 2 ppm by 23-27% in
    males after 1, 3 and 5 weeks and by 25-72% in females after all
    sampling intervals. Inhibition (39%) of plasma cholinesterase also
    occurred in females at 0.8 ppm after 1 and 3 weeks. Activity of brain
    cholinesterase was reduced (20%) only in females at 2 ppm after 3, 5
    and 8 weeks. There were no significant differences between control and
    treated groups in values of hematocrit, haemoglobin and total white
    blood count determined terminally. At the conclusion of the study, no
    compound-related effects were observed with respect to absolute weight
    of kidney and liver and gross pathological changes. Histopathological
    evaluation of a variety of tissues from 5 males and 5 females of the
    control and top dosage groups revealed no morphological alterations
    attributable to treatment. The data suggested 0.32 ppm as a no-effect
    level for the study (Hutchison  et al 1968).

    Long-Term Studies

    Rat

         Groups of 50 male and 50 female 5-week-old rats (CRL: COBS CD(SD)
    BR) were fed dietary levels of technical phorate (84.5% pure) at 0, 1,
    3 or 6 ppm for 24 months to evaluate the chronic toxicity and
    potential carcinogenicity of the compound. Mortality appeared to be
    increased in females at 6 ppm and only 36% of animals in this group
    survived terminally. However, over 60% animals in all groups,
    including the control, lived at least 90 weeks. The only compound-
    related clinical signs observed in the treated groups were tremors
    following over-dosing (327% of all the intended dosage levels) during
    week 9. Growth was depressed in females at 6 ppm during the first 26
    weeks and again between weeks 74 and 102. Food consumption was not
    consistently affected in any dose-response pattern. Haematology,
    clinical chemistry and urinalysis performed at 6, 12 and 24 months
    indicated the only notable findings to be a decrease in erythrocyte,
    haemoglobin and haematocrit values in females of the top dosage group
    at 12 months. Dose-related inhibition (20%) of plasma cholinesterase

    was noted in males at 6 ppm at 12 months, in males of all treated
    groups at 24 months and in females at both 3 and 6 ppm at all sampling
    intervals (3,6,12 and 24 months). Erythrocyte cholinesterase was not
    significantly depressed (<20%) at any of the time intervals. Activity
    of terminal brain cholinesterase was reduced (>20%) in males at 6 ppm
    and in females at and above 3 ppm. At termination, females of top
    dosage group showed an increase in organ/body weight ratio of adrenal,
    brain, heart, liver and spleen. Gross pathological examination and
    histopathological evaluation of a variety of tissues including the
    aforementioned organs revealed the only apparent treatment-related
    effect to be a significant increase at 6 ppm (both sexes but
    particularly in males) in incidence of inflammation and epithelial
    hyperplasia of the forestomach. Tumour data indicated the most
    prevalent types of spontaneous tumours to be pituitary adenoma in both
    sexes and mammary tumours in females. There was no significant
    difference between control and treated groups in incidence, type and
    time of detection of tumours. The study demonstrated 1 ppm as a
    marginal no-effect level (Litton 1981b).

    COMMENTS

         In the available rat teratology study, phorate was found to be
    non-teratogenic at oral doses up to 0.25 mg/kg bw. A 90-day feeding
    study in rats with phorate sulphone indicated that this metabolite is
    more potent that the parent compound as an inhibitor of
    cholinesterases. Long-term studies in mice and rats revealed no
    carcinogenic activity. Additionally, the long-term study in rats
    indicated 1 ppm as a marginal no-effect level, with plasma
    cholinesterase being the most sensitive index of biological activity.

         No-effect levels have been established in rats and dogs. However,
    in view of the continued unavailability of studies to evaluate
    potentially delayed neurotoxicity, only a temporary ADI was allocated.

    TOXICOLOGICAL EVALUATION

    Level Causing no Toxicological Effect

    Rat : 1 ppm in the diet equivalent to 0.05 mg/kg bw

    Dog : 0.01 mg/kg bw

    Estimate of Temporary Acceptable Daily Intake for Man

    0 - 0.0002 mg/kg bw

    FURTHER WORK OR INFORMATION

    Required (by 1983)

         An appropriate delayed neurotoxicity study.

    Desirable

         Observations in humans.

    REFERENCES

    Blinn, R.C. Personal communication to the World Health Organization by
    1982      American Cyanamid Co.

    Hutchison, E.B., Fegle, H.C., McNerney, J.M. and Levinskas, G.J.
    1978      Report on sulphone of ThimetR systemic insecticide:ninety-
              day repeated feeding to albino rats(CL 18,161). Report from
              Central Medical Department, American Cyanamid Co. submitted
              to the World Health Organization by American Cyanamid Co.
              (Unpublished)

    Litton. Teratology study in rats. ThimetRphorate. Final report from
    1978      Litton Bionetics, Inc. submitted to the World Health
              Organization by American Cyanamid Co. (Unpublished)

    1981a     18-month chronic toxicity and potential carcinogenicity
              study in mice. Phorate. Final report from Litton Bionetics,
              Inc., submitted to the World Health Organization by American
              Cyanamid Co. (Unpublished)

    Litton. 24-month chronic toxicity and potential carcinogenicity study
    1981b     in rats. Phorate. Final report from Litton Bionetics, Inc.,
              submitted to the World Health Organization by American
              Cyanamid Co. (Unpublished)

    Newell, G.W. and Dilley, J.V. Teratology and acute toxicology of
    1978      selected chemical pesticides administered by inhalation.
              U.S. E.P.A. Report No. 600/1-78-003, January 1978 submitted
              to the World Health Organization by American Cyanamid Co.


    See Also:
       Toxicological Abbreviations
       Phorate (ICSC)
       Phorate (Pesticide residues in food: 1977 evaluations)
       Phorate (Pesticide residues in food: 1984 evaluations)
       Phorate (Pesticide residues in food: 1985 evaluations Part II Toxicology)
       Phorate (Pesticide residues in food: 1994 evaluations Part II Toxicology)
       Phorate (Pesticide residues in food: 1996 evaluations Part II Toxicological)