CAPTAFOL JMPR 1973
Explanation
This fungicide was evaluated by the 1969 FAO/WHO Meeting on
Pesticide Residues (FAO/WHO, 1970b) and a temporary acceptable daily
intake for man of 0-0.05 mg/kg estimated. Further information on the
absorption and distribution following oral administration was
considered desirable and studies to elucidate the effects seen in
teratogenicity experiments and the histologically apparent
abnormalities in liver and kidneys of rats administered captafol were
considered to be needed. The new date received on the residues deal
primarily with the fate of captafol in animal tissues and milk and
include results of supervised trials in additional crops. The expanded
agricultural uses of captafol justify extension of tolerances to
additional crops. The further information made available is summarized
in this monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
Biochemical aspects
One male and one female monkey, one male and one female dog and
three male and three female rats were administered a single dose of
captafol labelled with 14C in the C=0 groups. The dose given was
about 7 mg/kg to monkeys and dogs and 16 mg/kg to rats, and it
followed at least two weeks pre-treatment with unlabelled captafol.
Expired CO2 was collected from rats and blood samples were taken
periodically from dogs and monkeys. Urine and faeces were collected
from all species until animals were killed 96 hours after dosage. The
level of activity was measured in samples of urine, faeces, blood and
tissues and extracts were examined to determine the metabolites
present. About 80% of administered activity was excreted within 26
hours, the majority in urine. Only a trace was excreted in expired
CO2. Analysis of blood showed that absorption from the
gastrointestinal tract was rapid; the maximum concentration in blood
occurred after 10-15 hours. Only traces (0.05% of dose administered)
of activity were found in liver, heart, kidneys, muscles and fat
samples taken at autopsy. The rate of excretion was almost identical
in the three species, as were the chromatographic patterns of extracts
of faeces, urine and blood. Captafol was detected only in faeces.
Tetrahydrophthalimide was detected in faeces, blood and urine and
tetrahydrophthalamic acid in blood and urine. Captafol epoxide was not
demonstrable in urine, blood or faeces (Crossley, 1968).
A lactating goat was fed on diet containing 20 ppm captafol for
seven days following which it received three consecutive daily doses
of captafol labelled with 14C in the C=0 radicals. Examination of
urine, faeces, blood, tissues and milk showed that this species
metabolized captafol in a manner similar to rats, dogs and monkeys but
at a faster rate. The major part of the 0.5 mg/kg dose was eliminated
in 24 hours and there was no evidence of cumulation. At a dosage level
of 0.5 mg/kg bw, milk contained approximately 0.05 ppm
tetrahydrophthalamic acid but no captafol was detectable (limit of
method 0.0005 ppm) (Crossley, 1970).
Lactating cows were administered 14C labelled captafol orally
at-dosage levels equivalent to a dietary level of 0.5 and 1 ppm for 30
days. No captafol was detected in milk or tissues and the maximum
concentration of metabolites in milk and tissues was <0.01 ppm
(Anon., 1970).
TOXICOLOGICAL STUDIES
Special studies on teratogenesis
Hamster. Groups of 10 pregnant female hamsters were fed diets which
provided 0, 125, 250, 500 and 1000 mg captafol/kg bw/day on days 4-9
of pregnancy. Animals were killed on day 15 and the uterine horns
examined. Body weight gains were reduced between days 4-9 but
recovered by day 15. In the 125, 500 and 1000 mg/kg groups, two, two
and six females died during the test. The number of resorption sites
was increased in the 125 and 500 mg/kg but not in other groups. The
number of implantation sites was low in the 500 and 1000 mg/kg groups
and the fetuses were lighter than normal. No specific abnormalities
which could be attributed to captafol were detected at any of the
dosage levels, (Arnold et al., 1968).
Groups of 10 pregnant female hamsters received a single oral dose
of 0, 125, 250 and 500 mg captafol/kg, or 1000 mg/kg thalidomide. Half
of each group was dosed on day seven and half on day eight of
pregnancy. All were killed and examined on day 15. The positive
control and 250 and 500 mg/kg groups grew at a slower rate than
controls. The number of live fetuses in each litter was reduced in the
thalidomide and 250 and 500 mg/kg groups, and thalidomide and 500
mg/kg captafol caused an increase in the number of resorption sites.
No specific abnormalities attributable to captafol were found on
examination of fetuses. The positive control group did not show any
increase in fetal abnormalities (Arnold et al., 1968).
Groups of 3-20 pregnant hamsters were administered a single dose
of between 100 and 1000 mg captafol/kg bw on days seven or eight of
gestation or were dosed daily with a total of between 500 and 1500 mg
captafol/kg bw between days six and 10. They were killed and examined
on the fifteenth day of gestation. The highest dosage levels increased
maternal mortality and produced some abnormal fetuses but the lowest
(single) dosage levels and the multiple doses produced no indication
of teratogenic effect (Robens, 1970).
Short-term studies
Rat. Groups of 25 male and 25 female rats were administered captafol
by gavage at a level of 250 mg/kg between days 1-7, 396 mg/kg between
days 8-14, 667 mg/kg between days 15-21 and 1000 mg/kg between days
22-28. A group of 10 males and 10 females acted as controls. Captafol
was administered in the form of D1 foltan-4-Flowable, the composition
of which was not stated. Groups of five test animals were killed on
days seven, 14 and 21 and the remainder after 28 days. The food intake
and body weight gain of males were depressed at all dosage levels but
food intake only at the 1000 mg/kg level in females. The total
leucocyte count was depressed in both sexes at the 1000 mg/kg level;
the proportion of lymphocytes was decreased and neutrophils increased.
The 1000 mg/k.g level also elevated SGPT, depressed the activity of
serum alkaline phosphatase and increased the blood urea concentration;
these were unaffected by lower dosage levels. At autopsy of the 1000
mg/kg group distention of the stomach and intestines and erosion of
the gastric mucosa were noted. The spleen weight was markedly lower
in the 1000 mg/kg group than in untreated rats. Microscopic
examination of a wide range of organs and tissues failed to detect any
abnormalities attributable to captafol (Plank et al., 1972).
Comments
Biochemical studies demonstrate that captafol is rapidly absorbed
and rapidly excreted, mainly as metabolites, in urine. No accumulation
occurs in tissues. The metabolic pathway of the tetrahydrophthalimide
moiety is likely to be the same as that in captan but the fate of the
tetrachloroethylthiomoiety has not been examined.
A teratogenicity studies in hamsters was negative as were
previously reviewed teratogenicity studies in monkeys and rabbits.
The results of a test in rats that received increasing daily
doses of up to 1000 mg/kg/day over a 28 day period did not help to
elucidate the occurrence of the abnormalities seen in the kidneys and
liver in an earlier two-year rat study. It did, however, demonstrate
that at the highest dosage level a lymphocyte to neutrophil shift
occurred, an effect previously noted in the long-term experiment.
Although the results of studies requested have not yet been made
available there is sufficient evidence to allow the establishment of a
temporary acceptable daily intake.
TOXICOLOGICAL EVALUATION
Level causing no significant toxicological effect
Dog - 10 mg/kg bw per day
Estimate of temporary acceptable daily intake for man
0-0.05 mg/kg
RESIDUES IN FOOD AND THEIR EVALUATION
Use patterns
Submissions from five countries; Canada, Japan, Netherlands,
Australia and New Zealand list accepted agricultural uses for
captafol. Also the basic manufacturer submitted product labelling for
the United States of America and France which reflect current usage in
those countries. The information on hand indicates that the fungicide
is used on some 22 new commodities, in addition to the eight
commodities evaluated in 1969.
The information available on agricultural uses in the responding
countries is sometimes fragmentary and shows a disparity in spray
concentrations, spray volume, frequency and timing of treatment, and
pre-harvest intervals, Table 1 contains a summary of the overall crop
uses, showing the range in each use parameter whenever possible.
TABLE 1
Crop Application Number of Pre-harvest
rate. (a.i.) applications interval - days
Apples, pears 0.12-0.62% 1-4 7-15
1.4 - 22 kg/ha 1 pre-bloom
Aspagus)
Carrots)
Beans) 0.096-0.14% Na(1) none
Eggplant)
Cabbage 0.8-1.5 kg/ha 4 10
Celery 0.1-0.24% Na 0-14
Citrus 0.1-0.5% 1-4 7-15
Coffee 0.6% 2-4 none
Cranberries 5.5 kg/ha 3 50
Grapes 0.8-2.0 kg/6 5 1
Leeks 0.12% No 21
Lettuce 0.1-0.32% Na 0-14
Macadamia 0.2% 1-2 none
Nuts 12 kg/h.
Crop Application Number of Pre-harvest
rate. (a.i.) applications interval - days
Onions 0.1-0.15%
0.6-1.38 kg/ha 6 0-7
Pineapple (a) 0.48-1.6% 1
(b) 8.8 kg/ha 8 indefinite
Potatoes 0.1-0.3% 7-10 day none
0.8-17.6 kg/ha intervals
Pumpkins 0.8-1.0 kg/ha 7 1
Strawberries 0.7-1.0 kg/ha 5 1
Tea Na Na Na
Na - Not available
Note: (1) Larger dosages generally for single early season use
(2) Larger dosages generally for treatment when fruit not
present
(3) Treatment (a) is dip of transplani slips, (b) is foliar
spray. USA directions provide for treatment at planting and
once monthly for eight months. Because of long growing
period before harvest there would be an interval of at
least 12 months.
Residues resulting from supervised trials
The new residue data made available in most cases indicate that
the chemical entity measured was captafol, per se. Unless otherwise
noted the residue values cited are presumed to be captafol.
Apples and pears
Data were available from France, Japan, Netherlands, New Zealand
and the United States of America. The data is weakened in many cases
by long periods of fruit storage before analyses. Data are freely
extrapolated between apples and pears.
Estimated residue following approved use seven days before
harvest - 5 ppm.
Asparagus
No data. Because of the unique cultural practices and physical
characteristics of asparagus spears and because there are no data from
other crops which might be extrapolated to asparagus, no opinion
concerning residue levels is offered.
Beans
No data. Estimated residue - not possible.
Carrots
No new data on carrots was made available. In the 1969 evaluation
it was stated that carrots and radishes in field experiments did not
take up captafol residues as determined by an analytical method
sensitive to 0.05 ppm. (FAO/WHO, 1970). It would be consistent to
establish a uniform low level tolerance of 0.5 ppm for the root crops
which are under consideration at the 1973 JMPR.
Cabbage
Limited data from supervised trials indicate very low residues on
cabbage sampled 10 to 20 days after treatment. The low residues might
be attributed to the practice of stripping wrapper leaves prior to
harvest. Because the values reported from this single trial (0.01 to
0.14 ppm) are inconsistent with deposits from foliar applications on
other crops it would be desirable to have further field trials with
details of sample preparation before further consideration is given to
tolerances on cabbage.
Celery
No data.
Citrus
Uses on citrus are sharply divided into those which are applied
following when no mature fruit are present (primarily to avoid
reduction of quality of fresh fruit by spotting), and coverage sprays
with specified pre-harvest intervals ranging from 7-15 days. There are
ample data to show that residues from the first type of treatment will
not exceed 0.5ppm. Adequate data are not available to show residues
which are likely to result from the latter type of treatment.
Coffee
No data.
Cranberries
Data from the United States of America, which is the only country
indicating use on this crop, show that residues would not exceed 5 ppm
under the conditions of use.
Grapes
Some data on captafol residues when applied with captan are
available. However, the sampling schedule is not pertinent to the
pre-harvest interval accepted in some countries (see Table I).
Additional data on grapes, corresponding to the spray schedules now
permitted, should be obtained before further consideration is given.
Eggplant
There are no data on eggplant. In view of the similarity of
physical characteristics with tomato fruit and similarity of use
pattern, it can be concluded that the residue data on tomatoes would
apply. Data on tomatoes show that residues would not exceed 5 ppm.
Lettuce
No data are available for lettuce or similar leafy vegetables.
Macadamia nuts
Residue data from Hawaii, which is the only place where use is
indicated, show no detectable residues in nut meats above limits of
detection. A United States tolerance of 0.1 ppm has been established
to cover incidental contamination of macadamia nut meats.
Onions and leeks
Limited data from one country on bulb onions show only trace
residues (0.01-0.03 ppm) when application is made four and seven days
before harvest. Consistent with the opinion on other root crops under
consideration it can be concluded that residues on bulb onions will
not exceed 0.5 ppm. This opinion does not include green onions, spring
onions, or shallots in which aerial plant parts are consumed. Data
from Netherlands show residues on leeks at 8 ppm under good
agricultural practice (21 day PHI).
Pineapple
Data on fruit treated according to United States registered
labels show that residues would not exceed 0.1 ppm. This is a
restricted use in which no treatments are made after the eighth month
from planting. From planting to harvest of the first crop is about two
years. Reports from other pineapple growing areas indicate that sprays
may be applied up to harvest. Data from such treatments show high
residues (22 ppm whole fruit and 55 ppm in peel). Before further
consideration is given, additional information should be required on
world wide patterns of use.
Potatoes
Data show that residues on potatoes treated up to harvest will
not exceed 0.5 ppm.
Pumpkins
There are no data on pumpkins but previous data on melons and
cucurbits should support extension of present temporary tolerances on
these commodities to pumpkins.
Strawberries
Limited data from one country indicate initial deposits of about
3.5 ppm declining to 1-2 ppm in seven days. Before further action is
taken there should be additional information on agricultural uses and
more residue data.
Tea
A limited number of analyses of green tea and brewed tea are
available.
Residues in brewed tea are below limits of analytical
sensitivity. Residues on green tea approach 1.5 ppm. No information
has been provided at all on use patterns in tea growing countries.
Additional information on use patterns and residue data are required.
Fate of residues
The fate of captafol residues in animals, plants and soil was
reviewed in detail at the 1969 Joint Meeting (FAO/WHO, 1970). Certain
degradation mechanisms, including sulfhydryl reactions and hydrolysis
were recognized as producing tetrahydrophthalimide (THPI),
tetrahydrophthalamic acid, tetrahydrophthalic acid and dichloroacetic
acid residues in certain substrates. However, it was noted that
information was lacking on the absorption, distribution and identity
of metabolites in animal tissues following oral administration.
There is now information on the nature and fate of residues in
animals in two unpublished reports from the basic manufacturer which
describe radioisotope metabolism studies in a lactating goat
(Grossley, 1970) and in lactating cows (Chevron, 1970). These studies
are summarized as follows:
Goat study
A single goat received three consecutive daily doses of C14
labelled captafol (carbonyl position) at a level of 15 ppm in total
ration. The animal was equilibrated with unlabelled captafol for seven
days, and conditioned for a further five days prior to sacrifice. A
balance study was conducted on urine, faeces, blood, milk, organs and
muscle tissue. Activity in the various substrates was subjected to
solvent partitioning and metabolites were identified by paper and thin
layer chromatography. About 80% of the total administered dose was
accounted for. Eighty-five per cent of the excreted activity was in
the urine, 14% in the faeces and 0.3% in milk. A total of 0.83% of the
administered dose was found in the tissues. The predominant metabolite
in urine was tetrahydrophthalic acid along with other polar
metabolites including tetrahydrophthalamic acid.
0.3% of the applied dose was found in milk. None was parent
compound (limit of detection 0.0005 ppm) but residues of
tetrahydrophthalamic acid and tetrahydrophthalic acid were detected.
The average residue level for total metabolites in milk was 0.05 ppm
(expressed as tetrahydrophthalamic acid) but individual values
indicate that metabolite residues on the order of 0.1 ppm in milk
could be expected at this feeding level.
Residues in tissue accounted for only 0.83% of applied dose, of
which most (0.74%) was in muscle. This is equivalent to 0.012 ppm.
However, it should be noted that sacrifice was five days after C14
administration ceased. In view of the rapid elimination from the body
it would be reasonable to expect that the liver and kidney would have
held higher residues if slaughter had occurred earlier. The identity
of the radioactivity in muscle was not established but only 1% was
extractable with organic solvents, indicating it was not captafol or
tetrahydrophthalimide, but probably second or third order metabolites.
Cow study
Two groups of three cows each were fed C14-labelled captafol
(carboryl position) at levels equivalent to 0.3 and 1.0 ppm in total
ration for 30 days. Accountability of the total administered C14 dose
was achieved by monitoring the same excreta and tissues as described
in the goat study. Radio-activity in the substrates examined was
characterized by solvent partitioning and identified by TLC. The cow
study differs in two important respects from the goat study. The
animals were not equilibrated with unlabelled captafol before giving
the C14 compound, and they were slaughtered within 24 hours after
medication ceased. The C14 accountability was 84-101%, the major route
of excretion being in the urine. No parent captafol was detected in
milk or tissues at any time. Activity in the form of metabolites did
occur in milk but at no time exceeded 0.005 ppm as total metabolites.
A similar picture obtains with respect to tissue, where no parent
captafol was detected and total metabolite residues were <0.01 ppm.
Residues in meat and milk were dose responsive (in both cow and goat
work) and should permit interpolation or extrapolation to gauge
residues from other intake levels.
Comment
The goat and cow studies demonstrate that ruminants degrade and
excrete captafol in much the same manner as was previously shown for
the rat, dog and monkey (FAO/WHO, 1970b). Metabolism is somewhat more
rapid in ruminants and the relative proportions of the water-soluble
metabolite tetrahydrophthalic acid is greater in ruminants than in
monogastric animals.
There are no approved uses of captafol on primary forage crops.
Certain crop by-products, culls or offal could introduce small amounts
of residues into animal rations. No data were made available on
possible residues in offal such as citrus pulp. Potatoes containing
residues at the tolerance level (0.5 ppm) would contribute only 0.17
ppm to the total animal diet assuming a maximum of 30% potatoes in the
ration. Relating this intake level to the cow feeding study, it is
estimated that residues of metabolites in milk would be <0.005 ppm
and in tissues <0.01 ppm. It would therefore not appear necessary to
recommend practical residue limits for meat and milk.
Methods of residue analysis
The 1969 evaluation (FAO/WHO, 1970) discussed methods of analysis
available for captafol residues. There are published methods which
distinguish between captafol and the related fungicides captan and
folpet. References are given for methods which determine parent
captafol and two tetrahydrophthalic acid metabolites (Chevron, 1970a).
The 1969 monograph also noted that it would be desirable to have
a collaborative study to validate a method suitable for regulatory
purposes to determine captafol in the presence of captan and folpet.
No new information has become available on suitable methods.
Appraisal
Worldwide agricultural use of captafol has expanded to include 21
commodities other than the eight commodities for which temporary
tolerances were recommended in 1969. Seven countries have responded
with information on current use patterns and/or residue data. The data
would in many cases support the extension of the present recommended
tolerances on eight commodities to other crops.
The animal metabolism studies requested in 1969 are now available
and do not show the presence of any metabolites in milk or edible
tissues other than those which were previously known. No residues of
parent or the tetrahydrophthalimide or its epoxide occur in meat or
milk at the levels fed. Trace residues of the tetrahydrophthalamic
acid and tetrahydrophthalic acid do occur. Since captafol is not used
on primary forage crops it would not appear to be necessary to
recommend practical residue limits in meat or milk.
The information requested on effects of washing and processing on
residue levels, data on residues occurring in raw commodities in
commerce and the collaborative study on a regulatory method, have not
become available, but in the light of all the information now
available may not be regarded as essential.
RECOMMENDATIONS
The following temporary tolerances are recommended in addition to
those recommended in 1969 and are based on the pre-harvest intervals
indicated.
Temporary Pre-harvest
Food commodity tolerances interval
(in ppm) (in weeks)
Cranberries 8 50
Leeks 8 21
Apples and pears 5 7
Eggplants 5 1
Pumpkins 2 1
Carrots, onions (bulb), 0.5 0
potatoes
Macadamia nuts (shelled) 0.1 0
FURTHER WORK OR INFORMATION
Required (by 1976)
1. Further studies to assist evaluation of histopathological
changes in the kidneys and liver of rats.
2. Studies to investigate the lymphocyte-neutrophil shift
noted in previous experiments.
Desirable
1. Studies to investigate to metabolism of the
tetrachloroethylthio-moiety of captafol.
2. Data on effects of washing, peeling, and blanching on
residue levels in various crops.
3. Data on residue levels occurring in commodities moving
in commerce.
4. Additional residue data and information on agricultural
practices in user countries with respect to asparagus, beans,
cabbage, celery, citrus fruit, coffee, grapes, lettuce,
pineapple, strawberries, and tea.
REFERENCES
Anon., The fate of difolatan in lactating cows, Unpublished
1970 report submitted by Chevron Chemical Co.
Arnold, D., Kodras, R. and Fancher, O. E. Teratogenic study
1968 on difolatan technical in Golden Syrian hamsters.
Unpublished report of Ind. Bio-Test Labs submitted
by Chevron Chemical Co.
Chevron. The fate of difolatan in lactating cows unpublished
1970 report, Chevron Chemical Co. 30 October.
Chevron. Method RM6B Chevron method for the tetrahydrophthalamic
1970a acid and tetrahydrophthalic acid metabolite.
Crossley, J. Difolatan: fate in animals. Unpublished report
1968 submitted by Chevron Chemical Co.
Crossley, J. The fate of difolatan in a lactating vominant
1970 (goat). Unpublished report submitted by Chevron
Chemical Co.
FAO/WHO 1969 Evaluation of some pesticide residues in food
1970 FAO/PL: 1969/m/17/1
Plank, J. B., Wright, P. L. and Keplinger, M. L. Twenty-eight
1972 day target organ study with difolatan 4 flowable
in albino rats. S.O. No. S139591, S-331
Unpublished report of Ind. Bio-Test Labs submitted
by Chevron Chemical Co.
Robens, J. F. Teratogenic activity of several phthalimide
1970 derivatives in the golden hamsters. Toxicol. Appl.
Pharmacol., 16: 24
See Also:
Toxicological Abbreviations
Captafol (HSG 49, 1990)
Captafol (ICSC)
Captafol (PIM 097)
Captafol (FAO/PL:1969/M/17/1)
Captafol (WHO Pesticide Residues Series 4)
Captafol (Pesticide residues in food: 1976 evaluations)
Captafol (Pesticide residues in food: 1977 evaluations)
Captafol (IARC Summary & Evaluation, Volume 53, 1991)