PESTICIDE RESIDUES IN FOOD - 1984
Sponsored jointly by FAO and WHO
EVALUATIONS 1984
The monographs
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, 24 September - 3 October 1984
Food and Agriculture Organization of the United Nations
Rome 1985
FOLPET
Explanation
Folpet was evaluated by the Joint Meeting in 1969 and 1973 1/
and a full ADI of 0-0.1 mg/kg bw was allocated on the basis of the
no-effect levels taken exclusively from studies done by Industrial
Bio-Test Laboratories. The Joint Meeting in 1982 was not presented
with information on the validation of these studies and no additional
data were made available. The meeting was informed, however, that
certain replacements or new studies were in progress or were to be
initiated. Consequently, the meeting agreed that the ADI should be
replaced by a temporary ADI pending evaluation of the new studies.
Further work required by 1984 included short-term test in rats, a
12-month study in dogs, long-term studies in mice and rats, a
reproduction study in rats and teratology studies in rats and rabbits.
Some new studies were submitted and are reviewed in this monograph
addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
TOXICOLOGICAL STUDIES
Special Studies on Teratogenicity
Rat
A pilot study using mated CRL:COBS CD (S.D.) BR female rats
(8 per group was performed wherein Folpet was administered via gavage
at doses of 0, 20, 80, 320, and 640 mg/kg bw on days 6 through 19 of
gestation. No rats died. Clinical signs consisted of rales, excess
salivation, chromorhinorrhea, gasping, soft/liquid faeces, decreased
motor activity, dyspnea and distended gastrointestinal tract. Reduced
maternal body weight gains were recorded in the 80, 320, and 640 mg/kg
does groups, as well as reduced food consumption in the 320 and
640 mg/kg dose groups. Reduced average foetal body weight occurred
also at 320 and 640 mg/kg. No other compound-related effects or
external anomalies were observed (Christian & Hoberman, 1983a).
Groups of mated CRL:COBS CD (S.D.) BR rats (25 per group) were
administered 0, 10, 60 and 360 mg/kg bw Folpet (89 percent pure)
orally via gavage on days 6 through 19 of gestation. Rats were
observed for clinical signs of toxicity, abortion, death, body weight
change and food consumption. Animals were killed on day 20 and pups
delivered by caesarean section. The uterus was weighed and examined
for number of live/dead foetuses and early and late resorptions.
Clinical signs consisted of excess salivation, chromorhinorrhea,
1/ See Annex 2 for FAO and WHO documentation.
decreased motor activity, soft/liquid faeces, dyspnea and
urine-stained fur. Three rats in the high dose group dies, two from
intubation error. In the surviving rats no gross lesions were
attributed to Folpet. Pregnant rats given 10, 60 and 360 mg/kg gained
less weight during the dosing period than controls. Food consumption
was significantly reduced in the high dose groups only. The number of
implantations, live/dead foetuses, foetal viability, resorptions,
average foetal body weight per litter, foetal sex ration and number or
corpora lutea were comparable to controls. There were no differences
in gross external, visceral or skeletal anomalies between treated and
control groups and no compound-related effects on ossification were
seen (Christian & Hoberman, 1983b).
Rabbit
Groups of New Zealand white rabbits (20 per group), artificially
inseminated, were administered Folpet (89 percent pure) via oral
intubation at dose levels of 0, 10, 20 and 60 mg/kg bw on days 6
through 28 of gestation. Rabbits were observed for body weight gain,
food consumption and clinical signs of toxicity. Does which died were
autopsied. On day 29, does were killed and pups delivered by caesarean
section. The death of one doe at 60 mg/kg was considered to be related
to ingestion of Folpet. No other compound-related deaths occurred. One
doe in each of the low and high dose groups aborted on day 21 and 22
of gestation, respectively. One doe in each of the control and high
dose groups naturally delivered a litter on days 28 and 29,
respectively. Significant inhibition of maternal body weight gain and
food consumption was determined in the mid and high dose groups.
Average number of corpora lutea, implantations, resorptions, foetuses
per litter, sex ratio and dead/resorbed implantations per litter were
comparable among all groups. Male and female mean foetal body weights
decreased in the mid and high dose groups compared to the control
group. There was a significant increase in the incidence of
hydrocephalic foetuses. A total of four foetuses from three different
high dose litters also had skull, gastric and lung abnormalities
(Feussner et al., 1984).
Special Study on Carcinogenicity
Mouse
Groups of CD-1 (ICR derived) mice (80 males and 80 females per
group) were administered Folpet (93 percent pure) in the diet at dose
levels of 1 000, 5 000 and 12 000 ppm for 112-113 weeks. An untreated
control group consisted of 104 mice of each sex. Animals were observed
routinely for food consumption, body weight gain, pharmacological and
toxicological effects. Survival was unaffected by treatment. Body
weight gain was adversely affected at the mid- and high-dose. Food
consumption was sporadic and no dose-related effects were evident.
Haematological data at one year revealed no significant differences
between groups. However, haematological data at termination
demonstrated a possible macrocytic anaemia in high dose males and
females. Gross pathology at termination was unremarkable except for
duodenal lesions and related gastrointestinal abnormalities. A
positive dose-related increase in the incidence of duodenal adenomas
and adenocarcinomas was observed for the 5 000 and 12 000 ppm groups,
but not in the 1 000 ppm group. The incidence of duodenal tumours in
females and males, respectively, were 0 and 1 percent (controls), 2
and 3 percent (low dose), 10 and 12 percent (mid-dose), and 52 and 54
percent (high dose). High dose males also demonstrated an increased
incidence of jejunal adenocarcinomas. No other oncogenic or neoplastic
changes were evident in other tissues (Eisenlord & Wong, 1982).
Short-Term Studies
Rat
Groups of Sprague-Dawley rats (20 per sex per dose) were
administered Folpet in the diet at dosage levels of 0, 300, 1 000,
3 000, and 10 000 ppm for 13 weeks. Technical problems encountered in
the diet analysis preclude use of this data since the analysis could
not be verified according to currently acceptable standards (Reno
et al., 1981).
COMMENTS
The 1981 JMPR noted that the ADI for Folpet, established
originally in 1973, was based exclusively on studies performed by
Industrial Bio-Test Laboratories. Information on the validity of these
studies has not been provided. The 1982 JMPR required submission, by
1984, of the following studies: a 90-day oral study in rats, long-term
oral studies in rats and mice, a 12-month oral study in dogs, a
reproduction study in rats and teratology studies in rats and rabbits.
The Meeting evaluated the required teratological studies and some
additional mutagenicity data. Although teratogenic effects were not
observed in rats, the Meeting was unable to evaluate the significance
of teratogenicity observed in rabbits. Technical problems with the
study precluded the use of data from a new 90-day oral study in rats.
In view of the absence of the other required data and because of
concern over the possible teratogenicity in the rabbit, the meeting
withdrew the temporary ADI.
REFERENCES
Christian, M.S. & Hoberman, A.M. Teratology study in rats with folpet
1983a technical. Report from Argus Research Laboratories, Inc.
submitted by Chevron Chemical Co. to WHO. (Unpublished)
Christian, M.S. & Hoberman, A.M. Pilot teratology study in rats with
1983b folpet technical. Report from Argus Research Laboratories
Inc. submitted by Chevron Chemical Co. to WHO. (Unpublished)
Eisenlord, G.H. & Wong, Z.A. Lifetime oncogenic feeding study of
1982 Phaltan Technical in CD-1(ICR derived). Report from
Environmental Health and Toxicology, Chevron Environmental
Health Center, submitted by Chevron Chemical Co. to WHO.
(Unpublished)
Feussner, E.L., Hoberman, A.M., Johnson, E.M. & Christian, M.S.
1984 Teratology study in rabbit with folpet technical. Report
from Argus Research Laboratories, Inc. submitted by Chevron
Chemical Co. to WHO. (Unpublished)
Reno, F.E., Burdock, G.A., Serota, D.G., Voelker, R.W., Alsaker, R.D.,
1981 Milad, G.M. & Zurek, E.K. Subchronic toxicity study in rats.
Phaltan: Final Report. Report from Hazelton Laboratories
America, Inc. submitted by Chevron Chemical Co. to WHO.
(Unpublished)