385. Captafol (Pesticide residues in food: 1977 evaluations)

CAPTAFOL JMPR 1977

Explanation

This fungicide has been evaluated at the Joint FAO/WHO Meetings on
Pesticide Residues in 1969, 1973, 1974 and 1976 (FAO/WHO, 1970G,
1974G, 1975G, 1977G). A temporary acceptable daily intake for man of
0.05 mg/kg was estimated in 1973. The 1973 Meeting required further
studies (by 1976) to assist evaluation of histopathological changes in
the kidneys and liver of rats, observed in a long-term study, and to
investigate the lymphocyte-neutrophil shift noted in previous
experiments. In 1976, comments from the manufacturers were brought to
the attention of the Meeting, which was also aware of the existence of
recent studies of the mutagenicity of this compound. It was therefore
decided to re-evaluate the compound in 1977. The Codex Committee on
Pesticide Residues, at its 9th (1977) Session, requested the Joint
Meeting to re-examine the data on which its recommendations made in
1973 for maximum residue limits on cranberries, apples and pears were
based. The re-examination is discussed in the following monograph
addendum.

EVALUATION FOR ACCEPTABLE DAILY INTAKE

Special studies on mutagenicity

Captafol was investigated for mutagenic activity by the dominant
lethal study in mice and by the host-mediated assay in rats using a
histidine auxotroph of Salmonella typhimurium. Male mice were
treated with a single intraperitoneal injection of 1.5 or 3.0 mg/kg.
Each test and control group consisted of 12 mice housed with 3
untreated virgin females. During 6 weeks these females were replaced
by others. The number of implantation sites, resorption sites and
embryos was the same for treated as for control matings.

For the host-mediated assay 2 separate trials were conducted, using 3
males in each test group. The animals received daily oral intubations
at levels of 125 or 250 mg/kg for 14 days. An indicator micro-organism
recovered from the peritoneal cavity after a 3-hour residence showed
no increase in numbers of revertants (Kennedy et al, 1975).

Several pesticides including captafol were studied for mutagenic
activities in a microbial system. The effect on the mutagenic activity
of captafol of adding S-9 Mix or L-cysteine to the system was
investigated. The mutagenicity of captafol observed in Escherichia
coli WP2 hcr and TA 1535 disappeared after addition of S-9 Mix or
L-cysteine (Moriya et al., 1975).

Long-term studies

Rat

In a two year study with captafol added to the diet at 0 (70 males and
70 females), 250, 500, 1500 and 5000 ppm (35 females and 35 males at

each test level), there was growth depression at the 1500 and 5000 ppm
levels. Mortality was increased in the 5000 ppm group, with no males
left alive after 23 months. A lymphocyte to neutrophil shift was
observed in the surviving males of this group after 21 months. There
was an increase in the liver to body-weight ratio at the 500, 1500 and
5000 ppm levels at 12 months. An increase in this ratio was also seen
in males at 250 ppm. At the end of the experiment there was no longer
a significant difference at the two lower test levels. Significant
increases were also observed in organ weight and organ to body-weight
rations for kidney and adrenal of rats fed at 1500 and 5000 ppm.
Histopathology revealed liver changes characterized by degeneration of
hepatic cells, vacuolization, incipient fat alteration, and
infiltration by mononuclear cells. Kidney changes were characterized
by alterations in proximal and distal tubular cells, many giant forms
with large irregular nuclei being present. These changes in liver and
kidney were only seen in rats fed the two highest dose levels. No
other histopathological changes were associated with the
administration of captafol (Kohn at al., 1964).

COMMENTS

Captafol appears to be not mutagenic in a dominant lethal test in mice
and host-mediated assay in rats.

In a two-year study with rats a non-dose related increase in the
relative liver weight was evident in males after 12 months, but not at
24. The absolute liver weight of the males at 12 months was also
significantly increased at 250 ppm but this effect was not produced in
the 500 and 1500 ppm groups. The histopathological changes observed in
the liver and kidneys at 1500 and 5000 ppm were considered to be
features of long-term toxicity, sometimes seen in old rats.

It seems justified therefore to consider 250 ppm as a no-effect level
in rats. The temporary ADI for humans has been changed to an ADI for
humans at a higher value.

TOXICOLOGICAL EVALUATION

Level causing no toxicological effect

Rat: 250 mg/kg in the diet, equivalent to 12.5 mg/kg bw

Dog: 10 (mg/kg bw)/day

ESTIMATE OF ACCEPTABLE DAILY INTAKE

0-0.1 mg/kg bw

RESIDUES IN FOOD AND THEIR EVALUATION

Cranberries

The following comment of the 9th (1977) Session of the Codex Committee
on Pesticide Residues was referred to the Joint Meeting: "From the
data summarized in the 1973 Evaluations a MRL of 5 mg/kg appeared
sufficient. It was decided to refer this item back to the Joint
Meeting for a review of the available data and to see whether the
proposed MRL (8 mg/kg) could be lowered to 5 mg/kg."

The reason is not evident for the discrepancy between the conclusion
that residues on cranberries would not exceed 5 mg/kg (FAO/WHO 1974,
p. 125) and the recommendation for a MRL of 8 mg/kg (ibid. p. 130). It
is possible that 5 mg/kg was a typographical error. The limited data
available on which the 1973 recommendation was based, are shown in
Table 1 They show that in some cases the residues from good
agricultural practice would exceed 5 mg/kg. In consideration of the
normal variations in residue data, an MRL of 8 mg/kg would be
appropriate.

TABLE 1. Residues of captafol on cranberries (USA)

Application
Test Number Rate, kg a.i./ha Number Crop part Interval Residue,
& Location from last mg/kg
spray to
harvest,
days

T-944 5.12 2 mature 80 0.00
Mass. fruit 0.00

6.0 0.00
0.00

T-963 3 mature 33 1.1
N.J. 3.4 fruit 2.6

T-964 3 mature 34 4.7
Wisc. 5.4 fruit 5.8

T-965 2 mature 38 2.5
Mass. 4.0 fruit 2.0

T-1808 3 mature 56 0.81
Mass. 5.6 fruit 0.76

T-1809 3 mature 54 6.33
Wisc. 5.6 fruit 4.63

Apples, pears

The Codex Committee on Pesticide Residues at its 9th Session made the
Comment (para. 65, Alinorm 78/24): "In the 1973 Evaluations no residue
data for these products had been published. The Committee therefore
felt unable to comment and referred the matter back to the Joint
Meeting".

Table 2 contains data available to the 1977 JMPR. It has not been
ascertained whether these data are identical to those evaluated by the
1973 Meeting. Apple data are translated to pears.

It is necessary to relate these data to the information submitted to
the 1973 Meeting on national use patterns from Canada, U.S.A., Japan,
the Netherlands, Australia, and New Zealand. The U.S.A. registration
of captafol is only for dormant sprays. Other countries permit
multiple foliar sprays at concentrations ranging from 0.12 to 0.62%,
and with pre-harvest intervals ranging from 7 to 15 days. On the basis
of these very limited data, it in estimated that the half-life is 10 -
20 days, and that maximum residue deposits shortly after treatment
could approximate 17 mg/kg (Table 2, test no. 831). The highest spray
concentration in these trials was 0.25% as compared with sprays up to
0.62% registered in come countries. It would thus appear that the 1973
JMPR recommendation for a 5 mg/kg MRL with a 7 day PHI is not very
realistic. The available data do not permit any reliable estimates on
residue levels to be expected from current agricultural practices.

APPRAISAL

The Codex Committee on Pesticide Residues has referred questions on
previously recommended MRLs for captafol on cranberries, apples and
pears to the Joint Meeting.

No new data on cranberries have become available. A re-examination of
the limited data reviewed by the 1973 Meeting shows that residues
would in some cases exceed 5 mg/kg, and that the previously
recommended MRL of 8 mg/kg would be appropriate.

Data on apples made available to the 1977 Meeting were evaluated: it
has not been ascertained whether they are the same as those evaluated
by the 1973 Meeting. Information on national use patterns is rather
limited. Some countries have registered only dormant sprays or early
season use, while others permit multiple treatments with pre-harvest
intervals of 7-15 days after foliar sprays at concentrations ranging
from 0.12 to 0.62%. The available data indicate that the presently
recommended 5 mg/kg MRL based on a 7-day pre-harvest interval may not
be appropriate, but adequate information is lacking.

TABLE 2. Residues -apples, seasonal applications

0 1 2 3 5 7 10 20
Test No. & kg a.i./ Dilution No. of Crop Days Day Days Days Days Days Days Days
Location ha Lbs./ Apple. Part
100 gals. 100 gals.

589 3.5 1 9 Fruit 1.9 1.5 1.3 1.3
N.J. 2.5 1.8 1.4 0.9

590 2.6 1 12 Fruit 8 7 6 4
N.C.

707 7.0 2 13 Fruit 1.8 0.9
N.J. 1.6 0.8

712 1.5-3.1 0.5-1.0 15 Fruit 0.8
Mich. 0.5

713 5.7 1 5 Fruit 10.5
N.C. 8.6

831 4.4 1.25 12 Fruit 13.7
N.J. 12.8

TABLE 2. (Continued)

0 1 2 3 5 7 10 20
Test No. & kg a.i./ Dilution No. of Crop Days Day Days Days Days Days Days Days
Location ha Lbs./ Apple. Part
100 gals. 100 gals.

13 Fruit 14.5
8.7

13 Fruit 17.5
13.2

1185 2.6 0.75 9 Fruit 2.7
England 2.3

1187 1.5 0.8 14 Fruit 2.9
France 3.0

1188 2.6 4 5 Fruit 2.3
New Zealand 3.8

1189 2.0 2.25 7 Fruit 1.2
New Zealand 1.8

1357 4.4 1 6 Fruit 4.7
N.C. (plus one dormant spray at 26 kg/ha) 6.6
(6 1b/100 gals)

NOTES

All samples mature fruit.

Formulation used was Difolatan (wettable).

RECOMMENDATIONS

1. The 1973 recommendation for maximum residue limit of 8 mg/kg for
captafol on cranberries, based on a 50 day pre-harvest interval, is
maintained.

2. The previously recommended maxim= residue limit of 5 mg/kg for
captafol on apples and pears is retained until additional information
becomes available.

FURTHER WORK OR INFORMATION

DESIRABLE

1. Further studies to investigate the metabolism of the
tetrachloroethylthio moiety of captafol.

2. Additional information on national use patterns and data from
supervised residue trials, particularly on apples and pears, from
countries where the product is used.

3. Further data on the effects of washing, peeling, and blanching on
residue levels in various crops.

4. Information, some of it from studies now in progress, on new
methods for the analysis of the parent compound together with the main
metabolites in products of animal origin.

5. Results of studies now in progress on the level and nature of
captafol residues in meat, milk, poultry and eggs.

6. Results of studies now in progress on the fate of captafol residues
in citrus fruits and citrus pulp.

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.

FAO/WHO (1975) 1974 evaluations of some pesticide residues in food.
AGP:1973/M/11; WHO Pesticide Residues Series, No. 4.

FAO/WHO (1977) 1976 evaluations of some pesticide residues in food.
AGP:1976/M/14.

Kennedy, G.L.Jr., Arnold, D.W. and Keplinger, M.L. (1975) Mutagenicity
studies with captan, captafol, folpet and thalidomide. Fd. Cosmet.
Toxicol. 13, 55-61.

Kohn, F.E., Key, J.H. and Calandra, J.C. (1964) Two-year chronic oral
toxicity of RE 5865-Albino rats. Unpublished report of Industrial
Bio-Test Laboratories submitted by Chevron Chemical Go.

Moriya, M., Kato, K., Shirasu, Y. and Kada, T. (1975) Mutagenicity
screening of pesticides in microbial systems. III. Fate of
mutagenicity. Mutation Research, 38, 333-354. (Summary only)

    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 3)
       Captafol (WHO Pesticide Residues Series 4)
       Captafol (Pesticide residues in food: 1976 evaluations)
       Captafol (IARC Summary & Evaluation, Volume 53, 1991)