METHACRIFOS

    EXPLANATION

    First draft prepared by Dr S. Caroldi
    University of Padua, Padua, Italy

         Methacrifos toxicity has been reviewed four times by the JMPR
    between 1980 and 1988 (Annex 1, FAO/WHO 1981ab, 1983ab, 1986d, 1987a,
    1988c, and 1989a).  Data include pharmacokinetic studies in rats;
    in vitro and in vivo genotoxicity studies; acute studies in mice,
    rats, rabbits, dogs, and hens; short-term toxicity studies in rats,
    dogs, pigs, and quail; carcinogenicity studies in mice and rats,
    teratogenicity studies in rats and rabbits;  delayed neurotoxicity
    tests in hens; and a four-week oral study in humans.

         A temporary ADI was allocated in 1980 which was extended in 1982
    upon receipt of some of the required data.  In 1986, further data were
    received including the study in humans.  The temporary ADI was again
    extended, pending receipt of a multigeneration reproduction study.  In
    addition, further data pertaining to the long-term rodent studies were
    required.  The data on the long-term studies were reviewed in 1988,
    and the temporary ADI was again extended.  The use of the data from
    the study in humans permitted the temporary ADI to be increased.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Toxicological studies

    Reproduction study

         In a 2-litter, 2-generation reproduction study, groups of 32
    (F0) male and female rats (Charles River strain) approximately 6
    weeks old received methacrifos (purity 95.1%) a mixed in the diet at
    0, 10, 100, and 200 then 400 ppm.  Depending on body weight
    variations, the calculated daily intake of methacrifos varied between
    0.5-1.5 mg/kg bw at 10 ppm, 4.1-15.5 mg/kg bw at 100 ppm, 8.4-34.1
    mg/kg bw at 200 ppm and 18.7-49.2 mg/kg bw at 400 ppm.  The highest
    dose corresponds to a daily intake lower than 1/10 of oral LD50 in
    rats (678 mg/kg).  Due to the instability of methacrifos in dietary
    preparations, test diets were prepared biweekly.  Dietary analysis
    performed throughout the whole test showed variations of methacrifos
    concentration within 15% of nominal values.  Rats were maintained on
    their respective diets for at least 70 days prior to mating.  The
    highest concentration of methacrifos was maintained for the F0
    generation up to weaning of F1a litters.  Then it was reduced to 200
    ppm two weeks before remating of F0 generation because selection of
    a F1 generation was not possible.  The F1b generations were
    maintained on their respective diets for 84 days prior to mating. 
    Histopathology of the reproductive tract was performed on F0 and F1b
    control adults, on animals dosed with the highest methacrifos dose and
    in any apparently infertile rats.  Occasional body tremors were
    present at different times in 3 out of 32 females of the 400 ppm
    group.  Cholinesterase activities were not measured.  In rats
    maintained on the 400 ppm methacrifos diet, body weight gain during
    lactation was lower than in controls (this corresponded to lower food
    consumption).  Lower body weight gain was also recorded at the
    beginning of exposure and during the mating period in this group. 
    Mean body weight was not different between groups except for males and
    females of F1b generation at the 4th week of age at the highest dose
    (lower than in controls).  Mating performance and the duration of
    gestation were normal.  Fertility index was slightly reduced at
    400/200 ppm for F0 generation at both matings.

         Litter parameters were severely affected at 400 ppm.  There were
    6 total litter losses post-birth with reduction of total and live
    litter weight at birth.  The viability index and lactation index were
    reduced.  Development during the pre-weaning stage was reduced;
    reduced stomach contents and reduced adipose tissue at sacrifice of
    weanlings indicated a nutritional deficit.  Selection of a subsequent
    generation at 400 ppm was not possible and the dose was reduced to 200
    ppm.  At 200 ppm total litter losses over the three matings were 3, 1,
    and 3 respectively.  Litter size, viability index and lactation index

    (only F1b generation) were reduced.  Mean pup weight was lower during
    lactation, the difference becoming more pronounced by weaning.  At 100
    ppm total litter losses over the four matings were 2, 0, 3, and 2,
    respectively.  A decreased fertility index was observed in the F1b
    parental females.  At 100 ppm a difference in litter size was
    occasionally observed (F1b generation only). Other litter parameters
    were not different from controls.  At 10 ppm no litter losses occurred
    and all litter parameters were unaffected.  Two litter losses were
    recorded in controls, one for each mating of the F0 generation. 
    Sporadic significant delay to achieve surface, startle and air
    righting reflexes at 100 ppm and 200 ppm were considered as secondary
    effects related to lower pup weights.  Organ weight analysis showed
    lower heart, spleen and ovary weights for females at 400/200 ppm. 
    Microscopic examinations of reproductive tracts of controls and of F0
    (400/200 ppm) and F1b (200 ppm) generations did not reveal treatment
    related changes.

         Toxic effects were observed in adults and resulting offspring at
    dose levels in the diet of 100 ppm and above and thus 10 ppm  (equal
    to 0.5 mg/kg bw/day) represented a NOAEL in terms of both adults and
    offspring (Penny et al., 1989).

    COMMENTS

         The present Meeting reviewed a reproduction study in rats.  The
    NOAEL was 10 ppm.  At higher levels, an increased incidence of total
    litter losses occurred, and in the F1b generation, reduced fertility
    and litter size were observed at the next dose level.

         The evaluation of the reproduction study alleviated previous
    concerns regarding reproductive toxicity.  The Meeting therefore
    allocated an ADI, based on the study in humans using a safety factor
    of 10.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    100 ppm in the diet, equivalent to 15 mg/kg bw/day
         Rat:      10 ppm in the diet, equivalent to 0.5 mg/kg bw/day
         Dog:      100 ppm in the diet, equivalent to 2.5 mg/kg bw/day
         Man:      0.06 mg/kg bw/day

    Estimate of acceptable daily intake for humans

         0-0.006 mg/kg bw

    Studies which will provide information valuable in
    the continued evaluation of the compound

         Further observations in humans

    REFERENCE

    Penny, J., Keith, J., Parker, C.A., Offer, J.M., Anderson, A., Dawe,
    I.S., (1989).  The effect of technical CGA 20168 on reproductive
    function of two generations in the rat.  Performed by Huntingdon
    Research Centre Ltd. CBG 449/89533.  Submitted to WHO by Ciba-Geigy
    Corp. 

    See Also:
       Toxicological Abbreviations
       Methacrifos (Pesticide residues in food: 1980 evaluations)
       Methacrifos (Pesticide residues in food: 1982 evaluations)
       Methacrifos (Pesticide residues in food: 1986 evaluations Part II Toxicology)
       Methacrifos (Pesticide residues in food: 1988 evaluations Part II Toxicology)