METHACRIFOS
EXPLANATION
Methacrifos was first evaluated for acceptable daily intake by
the Joint Meeting in 1980 and subsequently reviewed in 1982 and 1986
(FAO/WHO 1981b, 1983b, 1987a). A temporary ADI, allocated in 1980, was
extended in 1982 and 1986 pending: (1) the submission, by 1989, of an
adequate multigeneration study in rats, and (2) the submission of all
dietary preparation and analytical data for the oral toxicity study in
rats and the carcinogenicity study in mice, previously accepted by the
1980 Meeting. The latter have been submitted and are summarized in
this monograph addendum.
EVALUATION FOR ACCEPTABLE INTAKE
BIOLOGICAL DATA
Toxicological studies
Special study on carcinogenicity: diet preparation and dietary
analysis
Mice
Diet preparation records and analytical reports from the analyzed
samples have been submitted. Signed and dated records of weekly diet
preparation are available from week 43 to the end of the study
(week 92). Diets were prepared as a premix of technical product
(50 mg/ml acetone) which was added to the appropriate amount of diet
to obtain desired diet concentrations (1, 10 and 100 ppm). Samples of
diet had been sent to Ciba-Geigy for analytical determinations so that
shipping forms are available from study weeks 35 through 52, and 58
through 92.
Analytical determinations of dietary concentrations of
methacrifos were made at months 0, 3, 6, 9, 12, and monthly thereafter
until the end of the study. Results show that dietary concentrations
were in the range of 80-120% of the theoretical concentrations except:
once in the 1 ppm diet (68%); twice in the 10 ppm diet (67 and 73%);
and three times in the 100 ppm diet (75, 77 and 76%). The time-
weighted averages of methacrifos concentrations were found to be
1.02 ppm, 9.4 ppm and 99.2 ppm (Kobel, 1987).
Long-tern study: diet preparation and dietary analysis
Rats
Records of diet preparation and analyses of the diet samples have
been reviewed. The diets were prepared as a premix of technical
product (0.10%) which was added to the appropriate amount of diet to
obtain desired diet concentrations (1, 10, and 100 ppm). Available
data show that diet was prepared fresh weekly, except on one occasion.
Shipping forms were available from study weeks 10 through 14, 19
through 22, and 33 through 105 (end of study).
Analytical determinations of dietary concentrations of
methacrifos were made at months 0, 3, 4 (for high-dose group only), 6,
9, 12, 13, 14, 15, 17 (weeks 74 and 75), and monthly thereafter. These
results show that the dietary concentrations were lower than expected;
values below 80% of the theoretical concentrations were found twice in
the 1 ppm (74 and 72%) and in the 100 ppm (46 and 0.74%) diets, and
once in the 10 ppm diet (74%). The reason for the very low values
found in the 100 ppm group diet were not discovered nor additional
analyses done (except once) to see whether this problem occurred at
other intervals. Compound intake (mg/kg bw/day) of treated rats
(female data in parentheses) decreased from 0.09 (0.10), 1.0 (1.02)
and 8.7 (9.2) during study week 1 to 0.03 (0.03), 0.32 (0.38) and 2.9
(3.5) at the end of the study in the 1, 10 and 100 ppm groups,
respectively (Kobel, 1987).
COMMENTS
A temporary ADI, allocated in 1980, extended in 1982 and 1986,
was based on a NOEL for rat and dog plasma cholinesterase activities.
Dietary preparation and analytical data from the chronic toxicity
study in rats and the carcinogenicity study in mice were reviewed. The
meeting concluded that these data were adequate and hence that the
oral exposure of animals had been adequate. Upon re-evaluation of
previous studies (JMPR 1986) the Meeting utilized available brain
acetylchol-inesterase inhibition data to establish NOAELs in mice,
rats and dogs rather than the data on plasma cholinesterase activity
used previously. Considering the fact that a multi-generation study in
rats is in progress, the Meeting maintained the temporary ADI, but at
a higher level based on human data.
TOXICOLOGICAL EVALUATION
Mouse: 100 ppm in the diet, equivalent to 15 mg/kg bw/day.
Rat: 100 ppm in the diet, equivalent to 5.0 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 TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN
0-0.003 mg/kg bw.
STUDIES WITHOUT WHICH THE DETERMINATION OF A FULL ADI IS IMPRACTICABLE
(to be submitted to WHO by 1989)
An adequate multigeneration study in rats.
STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED
EVALUATION OF THE COMPOUND
Further observations in man.
REFERENCES
Kobel, K. 1987. Documentation on analytical support in: "Chronic oral
toxicity study with CGA 20'168 technical in albino rats (Industrial
Bio-Test Laboratories, Inc., IBT No. 856010836)" and "Chronic oral
carcinogenic toxicity study with CGA 20'168 in Swiss white mice
(Industrial BIO-TEST Laboratories, Inc., IBT No. 8580-08937).
Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.
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: 1990 evaluations Toxicology)