FOLPET JMPR 1973
This fungicide was evaluated by the 1969 FAO/WHO Meeting on
Pesticide Residues (FAO/WHO, 1969) and a temporary acceptable daily
intake for man of 0-0.16 mg/kg estimated. Further studies were
requested on the metabolism of folpet, particularly the
trichloromethylthio-moiety, and on the effects of the compound on
reproductive physiology. Long-term studies of sufficient duration to
test for carcinogenic effects were also considered to be needed.
Further data.made available are summarized in this monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
In blood, the sulfonamide bond is hydrolyzed rapidly (Dye, 1969)
yielding phthalimide, which is further hydrolyzed to phthalic acid,
and a trichlormethylthio-moiety which is identical to that produced
during the biodegradation of captan and probably metabolized by the
same pathways (see monograph on captan).
Special studies on mutagenicity
Mouse. A dominant lethal mutagenic study was conducted using groups
of 12 male mice, aged 70-80 days, which were administered 0, 5 or 10
mg folpet/kg bw intraperitoneally. Each male mouse was then placed
with three untreated virgin females. These were removed after a week
and replaced by another three females. This was repeated for six
consecutive weeks. Females were killed a week after removal from the
male and the numbers of implantation sites, deciduomata and late death
resorption sites and embryos counted. The percentage of mated females
which became pregnant was slightly but not significantly lower in the
10 mg/kg group than in controls. The number of deciduomata was
slightly high during weeks two and three in the 5 mg/kg group but not
in the 10 mg/kg group, and during the fifth week in the 10 ppm group.
The findings in test animals otherwise compared well with those of
controls (Calandra, 1971).
Drosophila. Folpet was administered either by injection into male
drosophila or by leg feeding to larvae. The results showed that no
mutagenic changes could be produced in the system although a very weak
effect could not be excluded (Kramers and Knaap, 1973).
Special studies on teratogenicity
Groups of 2-13 pregnant hamsters were administered a single dose
of between 400 and 1000 mg folpet/kg bw on days seven or eight of
gestation or were dosed daily from the sixth to the tenth day with a
total of between 1000 and 2500 mg folpet/kg bw. They were killed and
examined on the fifteenth day of gestation. At the highest dosage
levels maternal mortality was increased and some abnormal fetuses were
produced but the lower dosage levels produced no indication of
teratogenic activity (Robens, 1970).
0, one and two mice died in groups of two mice which received
respectively 15, 20 and 50 mg/kg of folpet by intraperitoneal
injection. The LD50 appeared to be in the region of 20 mg/kg/day.
The structure of folpet is similar to that of captan. Hydrolysis
of the compound takes place rapidly the phthalimide residue being
metabolized to phthalic acid. The trichloromethylthio-moiety is
presumably metabolized by the same pathways as for captan.
Previous studies have demonstrated a fetotoxic effect with folpet
but no evidence of teratogenic activity was found with folpet or
phthalimide. Negative results were seen in a dominant lethal test
using mice and in a test for mutagenicity in which drosophila were
exposed to high dosage levels.
The LD50 of folpet by the intraperitoneal route was about 20
mg/kg compared with > 10 000 mg/kg by the oral route; further
investigation of the intraperitoneal toxicity would be of interest.
In view of the similarity of folpet to captan, the present
knowledge of the manner in which the trichloromethylthio-moiety is
metabolized and the adequate long-term studies available on captan
(see monograph on captan) an estimate can be made of an acceptable
daily intake by man.
Level causing no toxicological effect
Rat: 3200 ppm in diet equivalent to 160 mg/kg bw
Dog: 1000 mg/kg bw per day
Estimate of acceptable daily intake for man
FURTHER WORK OR INFORMATION
1. Investigation of the fetotoxic action of folpet.
2. Investigation of the intraperitoneal toxicity.
3. Information on the nature, level and fate of residues following
washing, blanching, storage, and thermal processing of treated crops.
4. Residue data obtained by the newer methods of analysis on the main
commodities for which tolerances have been recommended.
5. Information on the fate of folpet in the soil.
6. Further data on the levels of degradation products in relation to
residues of the parent compound.
7. Results of metabolism studies currently planned.
Calandra, J.C. (1971) Mutagenic study with folpet in albino mice.
Unpublished report of Ind. Bio-Test Labs submitted by Chevron Chemical
Dye, D.F. (1969) Folpet. Unpublished summary report submitted to FAO
and WHO by Chevron Chemical Co.
Kramers, P.G.N. and Knaap, A.G.A.C. (1973) Mutagenicity tests with
captan and folpet in Drosophila melanogaster. Mutation Research, 21:
Robens, J.F. (1970) Teratogenic activity of several phthalimide
derivatives in the golden hamster. Toxicol. Appl. Pharmacol., 16: