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    ACEPHATE

    EXPLANATION

         Acephate was evaluated for acceptable daily intake by the Joint
    Meeting in 1976 when an ADI of 0-0.2 mg/kg bw was allocated (Annex I,
    FAO/WHO, 1977b). The ADI was derived from no-effect levels based on
    studies performed by Industrial Bio-Test Laboratories (IBT). Further
    data were evaluated in 1982, when a temporary ADI of 0-0.003 mg/kg bw
    was allocated (Annex I, FAO/WHO, 1983a). The temporary ADI was reduced
    to 0-0.0005 mg/kg bw in 1984 (Annex I, FAO/WHO, 1985c) in view of the
    inadequacy of the multigeneration study and the lack of a delayed
    neurotoxicity study. An ADI at the level of 0-0.003 mg/kg bw was
    allocated in 1987 when multigeneration reproduction, delayed
    neurotoxicity and lifetime carcinogenicity studies were submitted for
    evaluation by the Joint Meeting (Annex I, FAO/WHO, 1988b). Since a
    cholinesterase study in human volunteers by IBT has been validated
    (Cavalli, 1978), it was reconsidered. Statistical analysis of
    in vitro cholinesterase inhibition data, which were previously
    reviewed by the Joint Meeting in 1984 (Annex I, FAO/WHO, 1985c), has
    also been reconsidered.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOCHEMICAL ASPECTS

    Effects on enzymes

         Regression analysis of in vitro data on inhibitory activity of
    acephate technical on brain and red blood cell (RBC) acetyl-
    cholinesterase (ACHE) and plasma cholinesterase (ChE) from rat, monkey
    and human tissues was performed. Calculated I50 are reported in
    Table 1 (Griffis, 1988).

    Table 1.  I50 values (37C, 60', pH 8.0) for acephate techmical
                                                                        

                                  I50 (mM)
                             (95% confidence limits)
                                                                        

                 Brain             RBC AChE          Plasma
                                                                        

    rat          1.25-1.72         1.04-1.47         2.84-5.22
    monkey       2.78-3.38         1.90-3.17         1.43-2.49
    human        3.88-5.22         2.41-2.87         1.56-1.76
                                                                        

    BIOLOGICAL DATA

    Special study on delayed neurotoxicity

         In two experiments, groups of 6 adult hens were given by gavage
    200 or 700 mg/kg bw acephate technical (98% purity). In each
    experiment a group of 3 hens received DFP (0.200 mg/kg bw i.m.). The
    control animals received only water. Twenty-four hours after dosing,
    brain neuropathy target esterase (NTE) and AChE of survivors were
    measured. Results are summarized in Table 2 (Wilson, 1988).

    Table 2. Hen brain NTE and AChE activities 21 hours after treatment
                                                                        

    Compound      Dose                        % control     
                  (no.)                   NTE           AChE
                                                                        

    acephate      200 mg/kg   (5)            74            18
    acephate      700 mg/kg   (3)            55            12
    DFP           0.2 mg/kg   (3+3)       43-46         33-41
                                                                        

    Toxicological studies

    Observations in humans

         Combinations of acephate and methamidophos were orally
    administered to human volunteers. They received either a combination
    (methamidophos/acephate) of 1:9 or 1:4 daily (divided in three equal
    doses). Controls (two males and two females) received corn oil. The
    1:9 group (three males and three females) was administered the
    combination for consecutive periods of 21 days at grading doses of
    0.1, 0.2 and 0.3 mg/kg bw/day followed by a 7-day recovery period
    after which the dose was increased to 0.4 mg/kg bw/day (females only)
    for 10 days. The 1:4 group (two males and two females) received the
    combination at doses of 0.1 and 0.2 mg/kg bw/day for 21 consecutive
    days. No effect was noted on RBC cholinesterase at any dose. In the
    1:9 group, plasma cholinesterase activity was affected at the
    0.3 mg/kg dose in males and only slightly at the 0.4 mg/kg dose in
    females. In the 1:4 group, both males and females showed decreased
    plasma cholinesterase at the 0.2 mg/kg dose level.

         The NOAEL in this study was determined to be 0.3 mg/kg bw of
    acephate in combination with 0.03 mg/kg bw of methamidophos or
    0.2 mg/kg bw of acephate in combination with 0.04 mg/kg bw of
    methamidophos (Garofalo, 1973).

         The validated raw data support the above conclusions regarding
    cholinesterase activities. The dosing is also supported by analysis of
    samples of blood and urine of the study subjects. No information was
    available to support the claim of no clinical effects at any of the
    administered doses (Cavalli, 1978).

    COMMENTS

         Acephate was evaluated for acceptable daily intake by the Joint
    Meeting in 1976 when an ADI of 0-0.02 mg/kg was allocated. The ADI was
    obtained on no-effect levels based on studies performed by Industrial
    Bio-Test Laboratories (IBT), most of which were later considered to be
    invalid. An ADI at the level of 0-0.003 mg/kg bw was allocated in 1987
    when multigeneration reproduction, delayed neurotoxicity and lifetime
    carcinogenicity studies were submitted for evaluation by the Joint
    Meeting.

         In vitro data showed minimal differences in the sensitivity of
    rat, monkey and human plasma cholinesterase and erythrocyte and brain
    acetylcholinesterase to inhibition by acephate.

         A study in humans demonstrated no effect on erythrocyte
    acetylcholinesterase at any of the dose levels used (up to
    0.3 mg/kg bw in combination with 0.03 mg/kg methamidophos or
    0.2 mg/kg bw in combination with 0.04 mg/kg bw methamidophos).

         Acephate caused inhibition of brain neuropathy target esterase in
    hens at a dose lower than the LD50. The Meeting was therefore aware
    of the possibility that in extreme conditions of exposure, which are
    unlikely to occur in food, acephate may have the potential of causing
    delayed polyneuropathy.

         The Meeting was also aware that methamidophos is found as a
    residue in crops treated with acephate.

         On the basis of the rat NOAEL (brain acetylcholinesterase), the
    rabbit NOAEL for teratogenicity, and the human volunteer study, the
    Meeting agreed to establish an ADI at a higher level.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXOLOGICAL EFFECT

         Rat:      5 ppm in the diet, equivalent to 0.25 mg/kg bw/day
         Dog:      30 ppm in the diet, equivalent to 0.75 mg/kg bw/day
         Rabbit:   3 mg/kg bw/day
         Man:      0.3 mg/kg bw/day

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0-0.03 mg/kg bw

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED
    EVALUATION OF THE COMPOUND

         Further observations in man.

    REFERENCES

    Cavalli, R.D. 1978. Data validation Industrial Bio-Test report
    no. 636-02498. A study on the effects of orthene and monitor on plasma
    and erythrocyte cholinesterase activity in human subjects during
    subacute oral administration. Submitted to WHO by Chevron Chemical
    Company, Richmond, CA, USA (Unpublished).

    Garofalo, M. 1973. A study on the effects of orthene and monitor on
    plasma and erythrocyte cholinesterase activity in human subjects
    during subacute oral administration. Industrial Bio-Test Laboratories,
    Inc. report no. 636-02498. Submitted to WHO by Chevron Chemical
    Company, Richmond, Ca, USA (Unpublished) (Validated by EPA, USA).

    Griffis, L.C. 1988. Statistical analysis of acephate in vitro
    cholinesterase inhibition data. Chevron Environmental Health Center,
    Inc. Submitted to WHO by Chevron Chemical Company, Richmond, CA, USA
    (Unpublished).

    Wilson, B.W. 1988. Cholinesterase and neurotoxic esterase studies in
    chickens with Chevron Acephate technical. Preliminary Report submitted
    to WHO by Chevron Chemical Company, Richmond, CA, USA (Unpublished).
    


    See Also:
       Toxicological Abbreviations
       Acephate (ICSC)
       Acephate (Pesticide residues in food: 1976 evaluations)
       Acephate (Pesticide residues in food: 1979 evaluations)
       Acephate (Pesticide residues in food: 1981 evaluations)
       Acephate (Pesticide residues in food: 1982 evaluations)
       Acephate (Pesticide residues in food: 1984 evaluations)
       Acephate (Pesticide residues in food: 1984 evaluations)
       Acephate (Pesticide residues in food: 1987 evaluations Part II Toxicology)
       Acephate (Pesticide residues in food: 1990 evaluations Toxicology)
       Acephate (JMPR Evaluations 2002 Part II Toxicological)
       Acephate (JMPR Evaluations 2005 Part II Toxicological)