CAPTAN JMPR 1977
Explanation
The Joint Meeting evaluated this fungicide in 1969 (a full revision of
the 1965 evaluation) and 1973 (FAO/WHO, 1970, 1974). An acceptable
daily intake of 0-0.1 mg/kg was established but further information on
the significance of hematomas in the foetus in relation to foetal
death and malformation was desired. Further data have been made
available and are summarized in this monograph addendum.
At the 8th (1976) Session of the Codex Committee on Pesticide
Residues, reservations were expressed by the delegations of the
Netherlands and the Federal Republic of Germany on the recommended
maximum residue limit of 40 mg/kg for apples and cherries. Residue
trials in those countries showed that residues mould not exceed 5
mg/kg on apples (Netherlands) or 15 mg/kg on cherries (FRG). The CCPR
decided to return the proposals for apples, cherries and pears to Step
6 and requested governments to send data.
The requested data were not available for the 1976 Joint Meeting, and
the 9th Session of the CCPR issued an urgent request to governments to
send data. Data were made available to the 1977 Joint Meeting from the
U.S.A. and the Netherlands, and are reviewed below.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Absorption, distribution, biotransformation and excretion
Captan was fed to a dairy cow during 4 days at a level of 5 mg/kg in
feed, amounting to a total dose of 0.454 g. Gas-chromatographic
analyses were carried out on milk and urine samples, collected 1 day
prior to feeding the fungicide, daily throughout the feeding period
and for 6 days thereafter. Residues of intact captan were not detected
in any of the milk or urine samples.
The detection limits were estimated to be 0.01 mg/kg for milk and 0.1
mg/kg for urine (St. John and Lisk, 1976).
TOXICOLOGICAL STUDIES
Special studies on mutagenicity
Captan showed both frame-shift and base pair substitution mutagenesis
in S. typhimurium strains (TA 1535 series, without excision repair).
Exposure to rat liver homogenate decreased the mutagenic activity of
captan (Marshall et al., 1976).
Captan was investigated for mutagenic activity by the host mediated
assay with S. typhimurium in rats after 14 days oral treatment (by
gavage) with 125 or 250 mg captan/kg b.w. No increases in the number
of reverant bacteria were obtained as compared with controls.
Two groups of 12 male mice received a single i.p. injection of 3 or 6
mg captan/kg b.w. in corn oil. For 6 consecutive weeks one male was
mated with 3 untreated females, which were replaced weekly. Females
were killed 1 week after removal from the breeding cage. No
differences were found in the numbers of implantation sites,
resorption sites or embryos between control and treated groups
(Kennedy et al., 1975 a).
The mutagenicity of captan was tested by reversion of histidine
auxotrophs of S. typhimurium in the peritoneal cavity of rats and
mice. Negative results were obtained with maximal tolerable s.c. or
oral doses of captan. The fluid mediated assay using blood and urine
also gave negative results. In vitro, human and rat blood inactivated
the mutagenic action of captan at a level of 500 µg/ml but not at 1000
µg/ml blood (Fiscor et al., 1977).
Captan caused His+ reversions (S. typhimurium), Try+ (E. coli
WP 2) and mitotic recombinations (Saccharomyces cerevisiae)
irrespective of metabolic activation. The unscheduled DNA synthesis
assay was positive in the presence of mouse liver homogenate.
In a dominant lethal test, groups of 20 adult male mice were fed 0,
1250, 2500 and 5000 ppm captan for 7 weeks. Each male was mated with
two virgin females for 7 days. These females were then replaced by two
others and this sequence was continued for 8 weeks. Females were
sacrificed at mid-term of pregnancy and each female was scored for
early and late foetal deaths and living foetuses. Captan was not
mutagenic in the mouse by the dominant lethal test.
In a heritable translocation test male mice were fed 0, 2500 or 5000
ppm captan in their diet for 8 weeks. After this treatment males of
each group were mated with 2 untreated females. The F1 males were
raised to maturity and 200 animals from each experimental group were
mated with 3 virgin females. These females were sacrificed 14 days
after mating and the number of total, live and dead implants was
determined. Males, classified as sterile, partially sterile or
non-breeder were re-bred and the same evaluation was made for the
second and third breeding. The data on the F0 and F1 generation's
fertility, breeding and litter size distribution as well as the data
on the F1 generations dead implants and re-breeding show that captan
tends to induce dose-related effects on the reproductive performance
of male mice (Simmon at al., 1977).
Special studies on teratogenicity
Groups of 6 female beagles were fed captan (89.6%; 0, 30 and 60 mg/kg
b.w.) throughout the gestation period. The graded levels of captan
were adjusted weekly on the basis of food consumption and body weight.
Litters were delivered normally and X-rays were taken of all pups at
birth. After whelping, three mothers from each test group were placed
on stock diet and the remaining ones received the test material
through the lactation period. Pups were killed at 8 weeks of age and
liver, kidneys, heart, brain, spleen, gonads and adrenal, thyroid and
pituitary glands were weighed and histological examination was
conducted on three pups of each sex per group. Following weaning the
mothers were killed and complete gross and histopathological
examination was performed on the same organs. No toxic signs or
effects on skeletal or organ structure were observed. The number and
development of pups were not different in treated and control groups.
Gross and histopathological examination and evaluation of organ weight
data revealed no alteration (Kennedy at al., 1975b).
Special studies on reproduction
See "Special studies on mutagenicity".
COMMENTS
The Meeting was aware of the existence of recent studies on the
mutagenicity and carcinogenicity of this compound. Since the
additional information was not available in detail, consideration of
this pesticide was deferred to a future meeting.
RESIDUES IN FOOD AND THEIR EVALUATION
Apples, pears
Permitted uses in the U.S.A. are as follows:
(a) multiple treatments with 0.12% spray, with no pre-harvest interval
(PHI)
(b) up to 8 lbs a.i./acre (9 kg/ha), dust treatment with no PHI
(c) 0.12% post-harvest fruit spray or dip
Most of the data made available from the U.S. dates from the mid-1950s
and much of it is not germane to the registered use patterns. Analyses
were by the colorimetric method of Kittleson (1952). Data from residue
trails approximating the maximum registered use conditions were
extracted from the body of data and are tabulated below (Table 1). The
sources of the original data were the two basic U.S. manufacturers,
California Spray Chemical Co. (now Chevron), and Stauffer Chemical Co.
It appears likely that the same data were evaluated by the 1969 Joint
Meeting (FAO/WHO, 1970).
TABLE 1. Residues in apples and pears from field treatments.
Crop Application rate no. of Days from residues,
treatments last spray mg/kg
Apples 0.12% 1 1 9.7
" " " " 7.4
" " " " 8.0
" " " " 12.3
" " " " 11.0
" " " " 13.6
" " " " 10.0
" " " " 10.6
" " " " 11.0
" " " " 11.4
" " " " 12.0
" " " " 10.1
Pears 0.12% " " 6.6
" " " " 5.1
" " " " 4.3
" " " " 5.6
" " " " 5.0
" " " " 7.5
" " " " 5.9
" " " " 6.0
" " " " 4.8
" " " " 5.7
" " " " 6.0
Apples 0.12% 10 1 6.0
" " " " 4.0
" " " " 6.0
" " " " 5.1
" " " " 5.8
" " " " 6.0
" " " " 5.7
" " " " 5.9
" " " " 5.9
Table 2 shows residues on fruit sprayed in the laboratory in an
experiment which simulates post-harvest treatments to control storage
diseases.
TABLE 2. Residues in fruit sprayed post-harvest with 0.12% solution of
a 50% WP formulation of captan
Crop captan, mg/kg Average, corrected for blank
pear
exp. 1 6.6, 5.1, 4.3, 5.6,
5.6 5.3
exp. 2 7.5, 5.9, 6.0, 4.8,
5.7, 6.0 5.9
apples
exp. 1 9.7, 7.4, 8.0, 12.3,
11.0, 13.6 9.9
exp. 2 10.0, 10.6, 11.0,
11.4, 12.0, 10.1 10.3
The primary U.S. Manufacturer submitted to the 1977 Meeting some more
recent (1976) data which consisted of four analyses of whole fruit.
The residues were from field sprays and were in the range 3.2-5.4
mg/kg.
The data indicate that maximum residues approximating 10-15 mg/kg
could be expected on fruit treated up to harvest with the 0.12% spray
as registered in the U.S. Maximum residues from the permitted
post-harvest sprays or dip could contribute additional residues
approximating 10 mg/kg. This apparently is the rationale for the
current 25 mg/kg U.S. tolerances for apples and pears.
The rationale for the 1969 Joint Meeting recommendation of 40 mg/kg
for apples and 30 mg/kg for pears is not clear. It would appear that
the recommendation was based on the highest residue reported, without
allowing for excessive dosages applied in the residue trials.
The proposal of the Netherlands delegation to the 8th Session of the
CCPR for a 5 mg/kg maximum residue limit would obviously be inadequate
for the uses permitted in the U.S.A. In the absence of data from other
countries it cannot be determined whether the recommended 40 mg/kg
would be required. It would therefore be appropriate for the 1977
Meeting to recommend that the present limits of 40 and 30 mg/kg on
apples and pears (respectively) be reduced to 25 mg/kg for each.
Cherries
The permitted U.S. uses are:
multiple treatments with 0.12 to 0.24% WP sprays, or 2 to 3 lbs. a.i.
per acre (2.2 - 3.3 kg/ha) as a dust, with no pre-harvest interval; or
0.12% post-harvest dip or spray
The limited data on cherries made available to the 1977 Meeting are
shown in Table 3.
TABLE 3. Residues of captan in cherries resulting from supervised trials
Application rate No. of treatments Pre-harvest Residue, mg/kg
interval,
days
0.12% 3 20 6.9
" 1 9 11.7
" 1 0 28.0
0.24% 1 9 25.0
" 1 0 53.0
0.12% 1 30 0.59
" 1 23 0.12
" 1 16 0.63
" 1 9 7.5
" 1 1 5.1
0.16 1 30 0.60
" 1 23 0.56
" 1 16 0.12
Only three of the analyses on cherries were on samples taken within
one day after treatment. No data on residues from post-harvest dips
were submitted. These data are not adequate to support the maximum
residue limit of 40 mg/kg recommended by the 1969 Joint Meeting, nor
the proposal to the 8th Session of the CCPR by the Federal Republic of
Germany that a limit of 15 mg/kg would be adequate.
APPRAISAL
Questions originally raised at the 8th Session (1975) of the Codex
Committee on Pesticide Residues and reaffirmed by the 9th Session were
referred to the 1977 Joint Meeting, with a request for the evaluation
of data to determine whether the recommendations for MRLs of 40 mg/kg
on apples and cherries and 30 mg/kg on pears could be reduced.
Reports of supervised residue trials in the USA and the Netherlands
were made available to the 1977 Meeting. A summary of the occurrence
of captan residues in apples, pears, and cherries in channels of
commerce in the USA and the Netherlands was also available.
The relatively low residues on which the reservations raised at the
1975 CCPR Session were based, were apparently due to the differences
in good agricultural practices in different countries. Some countries,
in particular the USA, require post-harvest treatments. On the basis
of available data, it was concluded that an MRL of 25 mg/kg would be
adequate to cover residues resulting from both field treatments and
post-harvest sprays or dips to apples and pears. The available data on
cherries were not adequate to support the proposed reductions to 15
mg/kg.
RECOMMENDATIONS
The previously recommended maximum residue limits for captan on apples
and pears are replaced by the single limit shown below.
The present recommended MRL of 40 mg/kg for cherries is maintained
until additional information on national use patterns and supervised
trails is submitted.
Commodity Limit, mg/kg
Apples, pears 25
FURTHER WORK OR INFORMATION
Desirable
1. Investigation of the significance of haematoma formation in the
foetus in relation to foetal death and malformation.
2. Details of recent studies on mutagenicity and carcinogenicity
mentioned in the Report of the 1977 Meeting (FAO/WHO, 1978), Section
4.7, "Toxicology".
3. Information on current national use patterns and corresponding
supervised residue trials.
REFERENCES
FAO/WHO (1970) 1969 evaluations of some pesticide residues in food.
FAO/PL:1969/M/17/1; WHO/Food Add./70.38.
FAO/WHO (1974) 1973 evaluations of some pesticide residues in food.
AGP:1973/M/9/1; WHO Pesticide Residues Series, No. 3.
Fiscor G., Bordas, S., Wade, S.M., Muthiani, E., Wertz, G.F., Zimmer,
D.M. (1977) Mannalian host and fluid-mediated assays of captan and
streptozotocin in Salmonella typhimurium. Mut. Res. 48, 1-16.
Kennedy, G.L., Arnold, D.W., Keplinger, M.L. (1975a) Mutagenicity
studies with captan, captafol, folpet and thalidomide. Fd.
Cosmet. Toxicol. 13, 55-61.
Kennedy, G.L., Fancher, O.E., Calandra, J.C. Nonteratogenicity of
captan in beagles. Teratology 11, 223-226.
Kittleson, A.R. (1952) Anal. Chem., 4:1173.
Marshall, T.C., Dorough, H.W., Swim, H.E. (1976) Screening of
pesticides for mutagenic potential using Salmonella typhimurium
mutants. J. Agric. Food Chem. 24, 560-563.
Simmon, V.F., Mitchell, A.D., Jorgenson, T.A. (1977) Evaluation of
selected pesticides as chemical mutagens. In vitro and in vivo
studies. Environmental Health Effects Research Series
EPA-600/1-77-028.
St. John, L.E., Lisk, D.J. (1976) A feeding study with captan
fungicide in the dairy cow. Bull. Environ. Cont. Toxicol. 16,
474-476.