FOLPET
EXPLANATION
Folpet was evaluated for acceptable daily intake by the Joint
Meeting in 1969, and reviewed in 1973, 1982, and 1984 (Annex 1,
FAO/WHO, 1970a, 1974a, 1983a, and 1985b). A toxicological monograph
was prepared by the Joint Meeting in 1969 (Annex 1, FAO/WHO, 1970b)
and monograph addenda were prepared in 1973 and 1984 (Annex 1,
FAO/WHO, 1974b and 1985c). The previously established temporary ADI
was withdrawn in 1984 because of possible teratogenicity and the
absence of 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 a teratology study in rabbits. These and other data have now been
received and are reviewed in this monograph addendum.
EVALUATION FOR ACCEPTABLE INTAKE
Toxicological studies
Special studies on carcinogenicity
Mice
Groups of 52 male and 52 female B6C3F1 mice were fed folpet
(89.0% pure) in the diet at 0, 0.1, 0.5, or 1.0% for 21 weeks and
thereafter at 0.1, 0.35, or 0.7% for 83 weeks. Dietary analyses at
weeks 0, 1, 13, and 26 showed that about 88 - 91% of the nominal
dietary concentrations were fed. Food consumption was depressed among
mid- and high-dose only during the first weeks of treatment. However,
body-weight gain was reduced in mid- and high-dose animals throughout
the study. Clear signs of toxicity, observed principally in high-dose
groups, were erythema, dry flaking skin, reddish fur discoloration,
and weeping skin, particularly in the first 21 weeks. There was no
apparent effect of treatment on leucocyte counts of suvivors at 52,
78, or 104 weeks. The longevity of mid- and high-dose groups was
reduced.
At necropsy, relative weights of the brain, heart, lungs, liver,
kidneys, and testes were increased in a dose-related manner,
reflecting the reduced body weight of treated animals. Macro-
scopically, a dose-related increase in the ulceration of the
non-glandular gastric mucosa and thickening of the gastric and
duodenal walls were observed. The jejunal wall was thickened in
mid-dose females and in the high-dose groups. Dose-related distension
of the duodenal lumen also occurred. From 79 weeks onward there was a
dose-related increase in the incidence of nodules or masses on the
luminal surface of the stomach or duodenum or on the duodenal serosa.
Microscopically, the mid- and high-dose groups exhibited
dose-related epidermal hyperkeratosis and acanthosis and oesophageal
hyperkeratosis. Increased areas of marked acanthosis and hyper-
keratosis of non-glandular gastric mucosa were also seen in the
mid-dose groups and the high-dose males. Microscopic gastric
ulceration occurred without apparent relation to dose. Dose-related
areas of atypical duodenal glandular hyperplasia and mucosal gland
proliferation were seen in all treated animals, but especially in the
males. These atypical hyperplasia were often associated with duodenal
adenomas or adenocarcinomas. Atypical glandular proliferation was seen
only occasionally in the jejunum of treated female mice.
Gastric papillomas and squamous cell carcinomas, which may have
been secondary to mechanical obstruction of the duodenal lumen, were
found in all groups of treated male mice, but not in control males. A
dose-related incidence of gastric papillomas was also found in all
treated female groups, but similar lesions occurred in 2/51 control
females. Duodenal tumours, adenomas, and adenocarcinomas were found in
all treated groups of both sexes, with an even more significant dose
relationship. A single case of jejunal adenocarcinoma occurred in the
highest-dose group.
Primary or metastic tumours of uncertain aetiology were found in
all treated male groups. However, the incidences of broncio-alveolar
adenomas and malignant lymphomas were less in all treated male groups,
suggesting a high incidence of these conditions in control male
animals (Rubin & Nyska, 1985a; Nyska, 1985).
Rats
Groups of 60 male and 60 female F-344 rats were fed folpet (89%
purity) in the diet at 0, 500, 1,000, or 2,000 ppm for 104 weeks. Test
diets were prepared weekly and analysed for folpet content regularly.
Food intake was generally less in all treated groups than in controls,
but only the mean body weights of treated males were lower than those
of controls throughout the study. There were no signs of toxicity
attributable to treatment during the study.
At necropsy, there was a tendency toward increased incidences of
gastric ulceration in treated groups, which was significant only in
female rats. Folpet exposure was also associated with an increased
incidence of ulceration of the non-glandular stomach of the high-dose
group. Histologically, folpet treatment produced hyperkeratosis of the
oesophagus of rats in the high-dose groups and of the non-glandular
stomach of animals in the mid- and high-dose groups. There was also a
slight increase in gastric ulceration in the non-glandular stomach of
both males and females in the high-dose groups. The incidences of
C-cell adenoma, benign mammary fibroepithelioma, and malignant
lymphoma showed a positive significant trend with dose; only the
latter neoplasms were statistically significant, but the incidences of
all remained within the range of spontaneous incidences of these
neoplasms in F-344 rats. Accordingly, the results of this study
indicate that folpet is not carcinogenic to F-344 rats
(Crown et al., 1985).
Special studies on mutagenicity
Folpet was mutagenic in E. coli strain PQ37, but inactive in
the presence of S-9 microsomal mix. It was without genotoxic activity
in Chinese hamster V79 cells and in somatic cell mutation and
micronucleus tests in mice. Results are presented in Table 1. Dietary
analysis confirmed the stability of folpet in the test diet for the
somatic cell mutation study (Slagowski & Leary, 1985a).
Special study on reproduction
Rats
In a 2-generation reproduction study, groups of 30 male and 30
female Crl:COBS/CD (SD)/Charles River rats were fed folpet (89.5%
pure) in the diet at 0, 200, 800, or 3600 ppm during growth, mating,
gestation, and lactation for 2 litters per generation. Mating was
allowed after 62 days of dietary exposure. The test diets were fed to
the F0 males until the end of the mating periods for the F1b
litters and to the F0 females until the weaning of the F1b
litters. Pups were sacrificed 21 - 23 days after parturition, with the
exception of those F1b pups selected to parent the F2 generation.
Mating of these F1b pups began after 12 weeks of dietary
exposure and the above sequence repeated. Gross necropsy was performed
on all parental rats and on the F1a, F1b, and F2b litters.
The test diet was changed 3 times per week and each batch was
analysed for folpet content. Analyses showed that the test diets
contained 79.9 - 101% of the nominal folpet concentration.
The body weights of the high-dose males (F0 and F1) and
females (F1) and of the pups from high-dose litters were depressed
by treatment. This effect was most marked in the adult males,
especially in the second generation. Food consumption was
correspondingly reduced. Treatment had no significant effect on
mating, fertility indices, pregnancy rates, litter sizes, pup weights,
growth, or litter survival rates. There were no treatment related
effects found at necropsy or on histopathological examination. Based
on the finding of reduced body weight at the high dose, the no-effect
level determined in this study was 800 ppm (Hardy & Richter, 1985;
Slagowski & Leary, 1985c).
Special studies on teratology
Rats
In a pilot study, groups of 6 pregnant CD rats were treated daily
with 10, 65, 420, or 2750 mg folpet/kg b.w. (88.6% pure) by
intragastric gavage during days 6 to 15 of gestation. The high-dose
treatment caused maternal toxicity, reduced maternal body-weight gain,
and reduced fetal weight, but the lower doses were without apparent
effect (Rubin, 1985a).
Table 1. Results of mutagenicity studies on folpet
Test Test
system organism Purity Concentration Results Reference
E. coli E. coli 90% 0.03, 0.10, positive Abir, 1986
PQ37 PQ371 0.3, 1.0
mutation µg/ml (-S-9)
3.0, 10.0,30.0 negative
µg/ml (+S-9)
Chinese V79 90.1% 0.125, 0.25, negative Bootman et al.,
hamster cells2 0.5, 1.0, 2.0 1986
fibroblast µg/ml (-S-9)
3.125, 6.25 negative
12.5, 50
µg/ml (+S-9)
Mouse T-strain 88.7% 0, 100, 1500, negative Moore & Brusick,
somatic male mice & 5000 ppm, (decreased 1985
cell C57B1/6 fed days 8.5 pup body
mutation female - 12.5 of weight and
mice gestation survival
occurred)
Mouse Charles 91.0% 10, 50, 250 negative Jacoby, 1985
micro-nucleus River CD-1 mg/kg
mice3
1 Positive controls using 0.0156 - 1.0 µg/ml 4-nitroquinoline-1-oxide or 0.156 - 10.0 µg/ml
2-aminoanthracene gave positive results.
2 Positive controls using 1000 µg/ml ethylmethane sulfonate (-S-9) or 10 µg/ml
7,12-dimethylbenzanthracene (+S-9) gave positive results.
3 A positive control using chlorambucil gave the expected response.
Subsequently, groups of 22 mated female Charles River CD rats
were dosed daily by oral gavage with 0, 150, 550, or 2000 mg
folpet/kg b.w. (91.1% pure) suspended in 0.5% acetic acid containing
0.5% carboxymethylcellulose from days 6 to 15 of gestation. The
animals were sacrificed on day 20 and the uterine contents were
removed for pathological examination. One dam of the high-treatment
group died, while clear signs of toxicity were observed in the rest of
this group, namely, soft faeces (21/21), staining of fur (4/21), and
perianal staining (8/21).
Food consumption was markedly decreased in the high-dose group
during treatment; it was decreased in the intermediate group only
during the first days of treatment. Maternal body weight was
significantly reduced in the high-dose group throughout the study, and
to a lesser extent in the mid-dose group. Mean gravid uterine weights
were significantly depressed in the high- and mid-dose groups, but
terminal maternal body weight (i.e. net of gravid uterus) was
significantly depressed only in the high-dose group. Pre- and
post-implantation losses were increased over controls in the mid-dose
group only, while fetal weights were reduced in the high- and mid-dose
groups. Fetal crown-rump length was decreased slightly in mid- and
high-dose groups. The high-dose group contained a single fetus (1/277)
with multiple major malformations. On sectioning, another fetus in the
high-dose group was found to have unilateral microthalmia. Hepatic
discolouration was significant in the high-dose group. Skeletal
anomalies occurred in all treated groups. Reduced ossification of
cranial and pubic bones, sternebrae, metacarpals, and metatarsals was
significant in mid- and high-dose groups. There was a dose-related
reduction in the ossification of the interparietal bone of all treated
groups. In addition, angulated ribs occurred in a dose-related manner
in all treated groups. As a consequence, this study did not
demonstrate a no-observed-effect level (Rubin & Nyska, 1985b).
Rabbits
In a pilot study, groups of 6 mated HY/CR female New Zealand
white rabbits were treated with folpet (91.1% purity) at 0, 10, 60, or
150 mg/kg b.w./day by intragastric intubation from day 6 to day 18 of
gestation, inclusively. A marked loss of body weight occurred at the
high dose. Although fetal size was not affected by treatment, fetal
death was more marked at the high dose.
Post-implantation losses were increased in the mid-dose group
(Rubin & Nyska, 1985c).
Subsequently, groups of 14 mated HY/CR New Zealand white rabbits
were treated with technical folpet (91.1% purity) suspended in 0.5%
carboxymethylcellulose in 0.5% acetic acid at 0, 10, 40, or
160 mg/kg b.w./day by oral gavage from day 7 to day 19, inclusive, of
gestation. Administered doses were corrected daily for body weight.
The dams were sacrificed at day 29 and their uterine contents removed
and necropsied.
The body-weight gain of high-dose dams was reduced after
initiation of treatment, while that of the mid-dose group was reduced
during the initial few days of treatment only. There was a
corresponding decrease in food consumption of the high-dose animals
during treatment.
No animals died during treatment. At necropsy, the gravid uterine
weight was significantly reduced in the mid- and high-dose groups.
Fetal death (post-implantation loss) occurred more frequently in the
high-dose group than in controls. The proportion of small fetuses was
also greater in this group, and the mean fetal weight was reduced, but
not significantly.
There was evidence of delayed skeletal maturation in the
high-dose group and, to a lesser degree, in the mid-dose group. The
incidence of bilateral lumbar ribs increased in an apparently
dose-related manner in the mid- and high-dose groups. Ossification of
caudal vertebrae, sternebrae, and long-bone epiphyses were reduced at
the high dose. Other minor skeletal variations were not apparently
related to treatment. There was no evidence of hydrocephalus in either
treated or control rabbits (Rubin, 1985b).
Groups of 20 artificially inseminated female Hazleton Dutchland
New Zealand white (Dla Hra; (NZW)SPF) rabbits were dosed by oral
gavage with a suspension of folpet (89.5% pure) in Tween 80 (10.5% by
weight) and carboxymethylcellulose (0.7% by weight) at a volume of
5 ml/kg b.w./day. The test material was administered at 60 mg/kg b.w.
daily by stomach tube, using the pulse-dose regime tabulated in Table
2, at selected days of gestation.
Table 2. Pulse-dose regime for teratology study in rabbits
Dosage
Treatment group (mg/kg b.w./day) Days of administration
I 0 7-18
II 60 7-9
III 60 10-12
IV 60 13-15
V 60 16-18
Analysis of dosage formulations, prepared daily, for folpet
content ranged from 87.8 to 104% of nominal dosage.
The dams were sacrificed on gestation day 29, necropsied, and
uterine contents examined. Animals which aborted or delivered (and the
single animal which died) during the study were subjected to similar
procedures.
The abortion of 2 rabbits which received folpet on days 7 - 9 and
10 - 12 of gestation may have been related to treatment. Otherwise, no
clinical signs of toxicity were observed during the study, although
the incidences of dams with soft or liquid faeces increased in all
treatment groups, usually after the treatment period. At necropsy, no
gross lesions were attributable to treatment. Maternal body weights,
however, were significantly reduced in all treated groups, although
less so in groups II and III than in the others. Food consumption was
correspondingly reduced. Treatment had no apparent effect on the rate
of abortion or on fetal resorption.
Average litter sizes were unaffected, as were average fetal
weights, the number of viable fetuses, and the sex ratio. A
significantly-increased incidence of fetuses with an irregularly
shaped fontanelle was observed in Group IV. The control incidence was
4.5%, but this variation did not occur in Groups II and V. It was
possibly related to treatment, but the significance of this effect was
not clear. There were no other significant variations in fetal skull
morphology, and the incidence of hydrocephalus was not increased in
any group. Gastric or pulmonary anomalies were not increased in any
groups. The results of this study indicate that folpet is not
teratogenic in rabbits at 60 mg/kg b.w./day (Feussner et al., 1985;
Slagowski & Leary, 1985b).
Short-term studies
Rats
In a pilot study, groups of 20 male and 20 female F-344 rats were
fed folpet (89% purity) in the diet at 0, 0.2, 0.4, or 0.8% for
13 weeks. During treatment, body weights and food consumption of mid-
and high-dose males and of high-dose females were significantly
reduced. After 10 weeks there were no significant differences between
treated and control groups, but there were dose-related decreases in
the following serum enzymes: alkaline phosphatase and alanine
aminotransferase in treated groups, aspartate-aminotransferase in all
treated males and in high-dose females, and lactate dehydrogenase in
all treated male groups. Blood urea and chloride levels were
increased, but total serum proteins were reduced in mid- and high-dose
male groups. Blood urea was reduced in treated females, while total
protein was reduced in the high-dose groups and albumin was reduced in
the mid- and high-dose groups.
Treatment-related irritation of the proximal gastrointestinal
tract was evident at necropsy, as was hyperkeratosis of the
non-glandular gastric mucosa. Slight acanthosis of the stomach
occurred in 1 female rat in each group.
The kidneys of mid- and high-dose male rats showed a slight but
dose-related increase in the number of foci of atrophic basophilic
renal tubules, which was considered to be unrelated to treatment
(Sela et al., 1982).
Groups of 20 male and 20 female Sprague Dawley rats received
folpet (purity unspecified) in the diet at 0, 0.03, 0.1, 0.3, or 1.0%
for 13 weeks. Half the rats in each group were then sacrificed, while
the remainder were administered the basal diet for 2 weeks, until they
too were sacrificed.
There were no signs of toxicity and no deaths occurred during the
study period. The growth of high-dose male and female rats was
significantly reduced throughout the treatment period. This growth
retardation was not recovered during the 2-week recovery period after
treatment. (Dietary analyses showed that achieved doses were 85 - 106%
of nominal values.) Food consumption and haematological parameters
were unaffected by treatment. There were no treatment-related
variations in serum hepatic enzyme levels or renal function
parameters.
At necropsy, high-dose groups of both sexes exhibited reduced
mean body weights. Their relative brain weights were also reduced,
while their kidney weights were increased. However, there were no
significant differences in the organ weights of those animals
permitted to recover for 2 weeks. No gross pathological findings
attributable to treatment were observed. However, histopathological
findings of acanthosis, hyperkeratosis, submucosal oedema, and
pleocellular inflammatory infiltrate, together with occasional focal
gastric erosions or ulcerations, were found in the non-glandular
stomachs of high-dose rats after 13 weeks of treatment. These lesions
were not evident in stomach sections of high-dose rats after the
2-week recovery period.
Based on reduced body weight and other effects seen in the
high-dose group, the 0.3% dose level was the no-observed-effect level
in this study (Reno et al., 1981; Leary & Tucker, 1982).
Dogs
In a pilot study, groups of 4 male and 4 female beagle dogs were
dosed orally with encapsulated folpet (89.8 - 91.1% purity) at 0, 790,
1800, or 4000 mg/kg b.w./day for 13 weeks. Treated dogs generally
consumed less food than controls. Body-weight gain, which was reduced
in all treated groups, was significantly depressed in the mid- and
high-dose groups. Vomiting and diarrhoea occurred in all treated dogs,
but these symptoms were especially marked in the intermediate- and
high-dose groups. Treatment-related physical changes, including poor
condition, abdominal distension, excessive salivation, and progressive
decrease in testicular size, were especially prevalent in mid-and
high-dose groups. All high-dose males and 1 high-dose female died or
were killed in extremis. Neurological examination of these dogs and
those males which survived 12 weeks of treatment was unremarkable, as
was ophthalmoscopy of survivors. Most dogs killed in extremis had a
leucocytosis and some had decreased serum phosphate levels; 1 dog had
normochromic normocytic anaemia. Surviving dogs exhibited decreased
serum calcium and total plasma protein concentrations but increased
serum chloride levels. At necropsy, most treated dogs had decreased
weights of the brain, liver, kidney, spleen, and testicles.
Pathological examination showed atrophy, depletion, and fibrosis
of the lymphatic and haematopoetic systems, gonadal degeneration with
prostatic atrophy and fibrosis, thyroid degeneration, and muscular
dystrophy (Barel et al., 1985).
In a subsequent study groups of 6 male and 6 female beagle dogs
received technical folpet (89.5% purity) orally in gelatine capsules
at 0, 10, 60, or 140 mg/kg b.w./day. The high-dose treatment rate was
reduced to 120 mg/kg b.w./day at day 50 due to poor food consumption
and reduced body-weight gain. After a year of treatment, the animals
were sacrificed and necropsied.
All high-dose and 3 mid-dose male dogs exhibited initial loss of
body weight. The mean body weights of the mid- and high-dose males and
females were reduced, although not significantly, throughout the rest
of the study in a dose-related manner. There were dose-related
decreases in food consumption of mid- and high-dose males for the
first 3 months and of the mid- and high-dose females for the first
month. Although food consumption of the males was subsequently
comparable to controls, there was a tendency for reduced food
consumption in treated female groups, but not in a dose-related
manner. Ophthalmoscopy, performed at 6 and 12 months, revealed no
effects of treatment.
There was a tendency for reduced male leucocyte counts at 1, 2,
3, and 6 months, but not at 9 or 12 months; however, these changes
were not significantly different from control values. Clinical
chemistry showed a significant decrease in mean serum cholesterol,
total protein, albumin, and globulin levels in mid- and high-dose male
groups. In high-dose female dogs, there were significantly reduced
mean serum protein, albumin, and cholesterol levels. Urinalysis showed
no significant treatment-related effects.
No significant treatment-related effects were found at necropsy
or subsequent histopathological examination. According to observed
body-weight changes, reduced food consumption, and serum biochemical
changes, the no-observed-effect level of this study was 10 mg/kg
b.w./day (Daly & Knezevich, 1986).
Long-term study
Rats
In a combined chronic toxicity and carcinogenicity bioassay,
groups of 60 male and 60 female Charles River Crl: CD(SD)BR albino
rats received technical folpet (89.5% purity) in the diet at 0, 200,
800, or 3200 ppm for 104 weeks. An interim sacrifice of 10 rats
randomly selected from each group was conducted at 52 weeks. Ophthal-
moscopy was conducted on all rats prior to initiation and at weeks 52
and 105. Blood and urine samples were collected from 10 rats/sex/group
at weeks 27, 78, and 104 for clinical and biochemical analysis and
urinalysis. Rats dying during the course of the study were necropsied
and subjected to the usual investigations.
Growth rates and survival were not significantly affected by
treatment, although there was a slight tendency for reduced body
weights in the high-dose females during the first year. Food
consumption was correspondingly reduced at this dose level. There were
no treatment-related ophthalmoscopic findings. Conventional haemato-
logical, biochemical, and urinalysis parameters were unaffected
by treatment.
At necropsy, there were no organ-weight changes attributable to
treatment. Histopathology revealed an increase in lesions of the
non-glandular stomach, principally hyperkeratosis and/or acanthosis,
but also erosion and/or ulceration in both high-dose treatment groups.
These lesions occasionally were accompanied by submucosal oedema and
submucosal inflammatory cellular infiltrate. As there were no other
significant histopathological findings, the no-observed-effect level
in this study was determined to be 800 ppm (Cox et al., 1985).
Observations in humans
In a retrospective mortality study, a cohort of 134 workers
occupationally exposed during manufacture of captan for up to 9 months
annually, and to folpet for up to 3 months annually, was studied.
There was an apparent increase in the total number of mortalities from
all causes (18) for the cohort, compared to the number expected from
US mortality rates (S.M.R. 164). The excess mortality was principally
attributable to cardiovascular disease and "external causes" unrelated
to occupation. Statistically-significant increases were not observed
for any specific cause of death, including neoplasia, but the number
of deaths was too few to evaluate cause-specific mortality. Lack of
adequate industrial-hygiene monitoring data precluded satisfactory
estimation of the historical exposures (Palshaw, 1980).
COMMENTS
The 1984 Joint Meeting withdrew the ADI for folpet because of
substantial deficiencies in its toxicological data base and because of
possible teratogenicity in rabbits. Two independent studies now
indicate that folpet is not teratogenic in rabbits, even at a dose
that is clearly maternally toxic. Folpet was also without apparent
effect on the reproduction of rats in a 2-generation reproduction
study, but it apparently reduced the body weight and survival of
murine pups.
Further mutagenicity studies have confirmed that folpet is
mutagenic in procaryotes in vitro. It is not genotoxic in the
Chinese hamster fibroblast or mouse micronucleus assays, and it did
not induce mouse somatic cell mutations in vivo.
A short-term feeding study in rats produced acanthosis,
hyperkeratosis, submucosal oedema and cellular infiltration, and
occasional focal erosions in the non-glandular stomach. These lesions
resolved 2 weeks after cessation of exposure and are suggestive of an
irritant effect of folpet treatment. Similar irritative effects were
found in a chronic feeding bioassay in rats but, significantly, there
was no indication of a carcinogenic response.
No remarkable pathology was seen in a 1-year feeding study in
dogs.
The carcinogenicity of folpet to mice has been demonstrated
further. Dietary exposure produced dose-related increases in gastric
papillomas and squamous cell carcinomas, duodenal adenomas, and
adenocarcinomas. Accompanying irritant changes, oesophageal
hyperkeratosis, acanthosis and hyperkeratosis of the non-glandular
gastric mucosa, microscropic gastric ulceration, duodenal glandular
hyperpalsia, and mucosal glandular proliferation were also present.
Although the 1984 Joint Meeting noted that folpet produced a
dose-related increase in the incidence of duodenal adenomas and
adenocarcinoams in CD-1 mice at dietary concentrations of 5000 and
12,000 ppm, but not at 1000 ppm, the present study clearly
demonstrated carcinogenicity in B6C3F1 mice at 1000 ppm. Duodenal
adenomas and carcinomas, observed in the previous study with CD-1
mice, occurred in all treatment groups. In addition, gastric
papillomas and squamous cell carcinomas occurred. The development of
squamous cell neoplasia may correspond to the hyperkeratotic changes
and acanthosis seen in rats. The other neoplastic changes may be
related to the localized effects of the compound. If tumour induction
is related to "swamping" of the gut and passage of large amounts of
irritant compound into the small bowel, the significance of the
lesions for man is limited.
An epidemiological study showed no evidence of neoplasia among
workers occupationally exposed to captan and to a lesser degree to
folpet during manufacture, but the data are inadequate to evaluate
long-term exposure to folpet in man.
Since the concern over the potential teratogenicity of folpet has
been resolved and the previous toxicological data deficiencies now
have been met, the meeting agreed to re-establish a temporary ADI.
TOXICOLOGICAL EVALUATION
LEVEL CAUSING NO TOXICOLOGICAL EFFECT
Rat: 800 ppm in the diet, equal to 40 mg/kg b.w./day.
Dog: 10 mg/kg b.w./day.
ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN
0 - 0.01 mg/kg b.w.
STUDIES WITHOUT WHICH THE DETERMINATION OF A FULL ADI IS
IMPRACTICABLE, TO BE SUBMITTED TO WHO BY 1988:
1. Investigations directed towards determining the mechanism of
gastrointestinal neoplasia. The dynamics of passage of the compound
through the stomach, rate of release, and time spent in the duodenum
should be studied at varying doses in mice and rats to investigate the
possibility that induction of adenocarcinoma is a local exposure
effect. An evaluation of whether 2 mechanisms are operating, 1 for
squamous and another for adenocarcinomatous lesions, should be made.
Noting that a jejunal tumour occurred only at the highest dose,
local administration of the compound (via a gut loop) would also be of
interest. This may be impractical.
2. Comparative studies of the metabolic fate of the
trichloromethylthio moiety in mice and rats.
STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED
EVALUATION OF THE COMPOUND
Further observations in man.
REFERENCES
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1986 using in vitro bacterial cell test system. Unpublished
report from Makhteshim Chemical Works Ltd. Submitted to WHO
by Makhteshim Chemical Works Ltd., Beer-Sheva, Israel.
Barel, Z., Nyska, A., & Waner, T. Folpan: 90-day preliminary toxicity
1985 study in beagle dogs. Unpublished report No. MAK/061/FOL
from Life Science Research Israel Ltd., Ness Ziona, Israel.
Submitted to WHO by Makhteshim Chemical Works Ltd.,
Beer-Sheva, Israel.
Bootman, J., Hodson-Walker, G., & Lloyd, J.M. Folpan Tech.:
1986 Investigation of mutagenic activity at the HGPRT locus in a
Chinese hamster V79 cell mutation system. Unpublished report
No. 86/MAK/054/188 from Life Science Research Israel Ltd.,
Ness Ziona, Israel. Submitted to WHO by Makhteshim Chemical
Works Ltd., Beer-Sheva, Israel.
Cox, R.H., Marshall, P.M., Voelker, R.W., Vargas, K.J., Alasker, R.D.,
1985 & Dudeck, L.D. Combined chronic oral toxicity/oncogenicity
study in rats: Chevron folpet technical (SC-1388).
Unpublished report No. 2107-109 from Hazleton Laboratories
America, Inc., Vienna, VA, USA. Submitted to WHO by Chevron
Chemical Company, Richmond, CA, USA.
Crown, S., Nyska, A., & Waner, T. Folpan. Carcinogenicity study in the
1985 rat. Unpublished report No. MAK/022/FOL from Life Science
Research Israel Ltd., Ness Ziona, Israel. Submitted to WHO
by Makhteshim Chemical Works Ltd., Beer-Sheva, Israel.
Daly, I.W. & Knezevich, A.L. A one-year subchronic oral toxicity study
1986 in dogs with folpet technical. Unpublished report
No. 82-2677 from Bio-Dynamics, Inc., East Millstone, NJ,
USA. Submitted to WHO by Chevron Chemical Company,
Richmond, CA, USA.
Feussner, E.L., Hoberman, A.M., Johnson, E.M., & Christian, M.S.
1985 Teratology study in rabbits with folpet technical using a
"pulse-dosing" regimen. Unpublished final report on Project
No. 303-004 from Argus Research Laboratories, Inc.,
Horsham, PA, USA. Submitted to WHO by Chevron Chemical
Company, Richmond, CA, USA.
Hardy, L.M. & Richter, W.R. SOCAL 2140 (S-2323): Two generation (two
1985 litter) reproduction study in rats with Chevron folpet
technical. Unpublished report from Chevron Environmental
Health Center, Inc. Submitted to WHO by Chevron Chemical
Company, Richmond, CA, USA.
Jacoby, O. Folpan. Mouse micronucleus test. Unpublished report
1985 No. MAK/071/FOL from Life Science Research Israel Ltd.,
Ness Ziona, Israel. Submitted to WHO by Makhteshim Chemical
Works Ltd., Beer-Sheva, Israel.
Leary, J.B. & Tucker, B.V. Phaltan 90-day dietary study in rats.
1982 Unpublished report (Hazleton Project No. 2107-100 and
Chevron Test No. S-1440/Diet Analysis) from Chevron Chemical
Company Agricultural Chemicals Division. Submitted to WHO by
Chevron Chemical Company, Richmond, CA, USA.
Moore, M.R. & Brusick, D.J. Evaluation of Chevron folpet technical in
1985 the mouse somatic mutation assay. Unpublished Project
No. 20994 from Litton Bionetics, Inc., Kensington, MD, USA.
Submitted to WHO by Chevron Chemical Company, Richmond, CA,
USA.
Nyska, A. Neoplasia in the stomach. Unpublished report No. MAK/015/FOL
1985 from Life Science Research Israel Ltd., Ness Ziona, Israel.
Submitted to WHO by Makhteshim Chemical Works Ltd.,
Beer-Sheva, Israel.
Palshaw, M.W. An epidemiologic study of mortality within a cohort of
1980 captan workers. Unpublished report from Stauffer Chemical
Company. Submitted to WHO by Chevron Chemical Company,
Richmond, CA, USA.
Reno, F.E., Burdock, G.A., Serota, D.G., Voelker, R.W., Alasker, R.D.,
1981 & Milad, G.M. Subchronic toxicity study in rats. Unpublished
report No. 2107-100 from Hazleton Laboratories America,
Inc., Vienna, VA, USA. Submitted to WHO by Chevron Chemical
Company, Richmond, CA, USA.
Rubin, Y. Folpan. Preliminary teratology study in rats. Unpublished
1985a report No. MAK/048/FOL from Life Science Research Israel
Ltd., Ness Ziona, Israel. Submitted to WHO by Makhteshim
Chemical Works Ltd., Beer-Sheva, Israel.
Rubin, Y. Folpan. Preliminary teratology study in the rabbit.
1985b Unpublished report No. MAK/051/FOL from Life Science
Research Israel Ltd., Ness Ziona, Israel. Submitted to WHO
by Makhteshim Chemical Works Ltd., Beer-Sheva, Israel.
Rubin, Y. & Nyska, A. Folpan. Oncogenicity study in the mouse.
1985a Unpublished report No. MAK/015/FOL from Life Science
Research Israel Ltd., Ness Ziona, Israel. Submitted to WHO
by Makhteshim Chemical Works Ltd., Beer-Sheva, Israel.
Rubin, Y. & Nyska, A. Folpan. Teratology study in the rat. Unpublished
1985b report No. MAK/049/FOL from Life Science Research Israel
Ltd., Ness Ziona, Israel. Submitted to WHO by Makhteshim
Chemical Works Ltd., Beer-Sheva, Israel.
Rubin, Y. & Nyska, A. Folpan. Preliminary teratology study in rabbits.
1985c Unpublished report No. MAK/050/FOL from Life Science
Research Israel Ltd., Ness Ziona, Israel. Submitted to WHO
by Makhteshim Chemical Works Ltd., Beer-Sheva, Israel.
Sela, J., Nyska, A., Pitel, Z., & Rambach, H. Folpan. Toxicity in
1982 dietary administration to rats for 13 weeks. Unpublished
final report No. MAK/021/FOL from Life Science Research
Israel Ltd., Ness Ziona, Israel. Submitted to WHO by
Makhteshim Chemical Works Ltd., Beer-Sheva, Israel.
Slagowski, J.L. & Leary, J.B. Addendum to an evaluation in the mouse
1985a somatic cell mutation assay with Chevron folpet technical
(SX-1388). Unpublished report (Litton Bionetics Project
No. 21994-491 and Ortho Test No. S-1971 diet analysis) from
Chevron Chemical Company, Ortho Agricultural Chemicals
Division, Development Research Department. Submitted to WHO
by Chevron Chemical Company, Richmond, CA, USA.
Slagowski, J.L. & Leary, J.B. Addendum to teratology study in rabbits
1985b with folpet technical (SX-1388) using a "pulse-dosing"
regimen. Unpublished report (Argus Research Laboratories
Project No. 303-004 and Ortho Test No. S-2512 dosage formula
analysis) from Chevron Chemical Company, Ortho Agricultural
Chemicals Division, Development Research Department.
Submitted to WHO by Chevron Chemical Company, Richmond, CA,
USA.
Slagowski, J.L. & Leary, J.B. Addendum to reproduction study in rats
1985c with folpet technical (SX-1388). Unpublished report (SOCAL
Project No. 2140 and Ortho Test No. S-2323 diet analysis)
from Chevron Chemical Company, Ortho Agricultural Chemicals
Division, Development Research Department. Submitted to WHO
by Chevron Chemical Company, Richmond, CA, USA.
See Also:
Toxicological Abbreviations
Folpet (HSG 72, 1992)
Folpet (ICSC)
Folpet (FAO/PL:1969/M/17/1)
Folpet (WHO Pesticide Residues Series 3)
Folpet (WHO Pesticide Residues Series 4)
Folpet (Pesticide residues in food: 1984 evaluations)
Folpet (Pesticide residues in food: 1990 evaluations Toxicology)
Folpet (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)