PESTICIDE RESIDUES IN FOOD - 1984
Sponsored jointly by FAO and WHO
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
Captan has been evaluated by the Joint Meetings on Pesticide
Residues in 1969, 1973, 1974, 1977, 1978 and 1982 (FAO/WHO, 1965b,
1970, 1974, 1975, 1979, and 1983). In view of the concerns with
respect to carcinogenicity in mice, the inability to demonstrate a
no-effect level in the 3-generation reproduction study in rats and the
finding of the long-term/carcinogenicity studies in both mice and rats
conducted by IBT being invalid, the 1982 Joint Meeting decided that
the full ADI be modified to a temporary ADI at 0 - 0.01 mg/kg bw.
Further work required by 1984 included the complete report of the new
two-year study in rats and mice, and a two-generation reproduction
study. New studies were made available to the meeting and are reviewed
in this monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
Special Study on Reproduction
Groups of Charles River CD rats (15 males and 30 females per
group) were fed Captan in the diet at dosages of 0, 6, 12.5 and 25
mg/kg/day in a one-generation, one-litter reproduction study. After
102 days of treatment the animals were mated. The F0 adults were
necropsied after weaning of the F1 pups. The parental rats and the
pups were observed for signs of toxicity, changes in general
behaviour, appearance and survival. There were no compound-related
effects on survival, appearance, behaviour, body weight or food
consumption among the parental animals. Fertility index, length of
gestation, and pup viability and weight at birth in all treated groups
were comparable to controls. Pup survival during lactation was
comparable to controls. There was slight reduction in mean pup body
weight and litter weight on lactation days 4, 7 and 14 at the 25 mg/kg
level. No other compound-related effects on reproduction were reported
(Aldrige, Shardein & Blair, 1982).
Special Study on Teratology
The Joint Meeting in 1982 reviewed a teratology study in Golden
hamsters in which "non-specified" rat anomalies were reported in
treated pups. Additional detail was requested and has been provided.
The rib anomalies were primarily bent ribs, confined to the high-dose
group and occurred in only one litter. The results of this study
indicated that Captan produced maternal deaths and weight loss at
doses of 200 and 400 mg/kg and was also foetotoxic at the 400 mg/kg
dose. Therefore, these bent rib anomalies may be accounted for by a
maternal stress effect upon the foetus rather than a teratogenic
effect (Shardein, 1983).
Special Studies on Carcinogenicity
Groups of CD-1 (ICR derived) mice (80 males and 80 females per
group) were fed Captan (purity 90.7 percent) in their diet at dose
levels of 0, 2 000, 6 000 and 10 000 ppm for four weeks, after which
these levels were increased to 0, 6 000, 10 000 and 16 000 ppm,
respectively, for the remaining 105 weeks of the study. In males there
was a statistically significant dose-related trend in mortality. The
survival pattern of females is less clear, but still statistically
significant, due to higher mortality of the high-dose group. In all
treatment groups, average body weights were significantly lower than
the controls throughout the study. No significant haematological
effects were noted.
Gross pathological examination demonstrated the presence of
duodenal lesions and gastrointestinal tract abnormalities. There were
statistically significant increases in duodenal adenomas and
adenocarcinomas in both sexes. The incidence of adenoma and carcinoma
in the stomach, duodenum and jejunum-ileum for males was 3.7 percent
(control), 23.7 percent (low-dose), 28 percent (mid-dose) and 48.7
percent (high-dose); for females, 3.7 percent (control), 32 percent
(low-dose), 26 percent (mid-dose) and 36 percent (high-dose). The
high-dose males generally showed proliferative changes of the duodenum
earlier than the other groups. The results demonstrate that captan, at
dietary concentrations of 6 000, 10 000 and 16 000 ppm induced both
benign and malignant duodenal tumours in CD-1 mice (Bradfield, Wong &
Groups of 42-day-old CD-1 mice (100 males and 100 females per
group) were administered Captan (purity 89 percent in the diet at dose
levels of 0, 100, 400, 800 and 6 000 ppm continuously for 22 months.
Cage-side observations for signs of toxic or pharmacologic effects
were conducted daily and palpations for tissue masses were performed
weekly. Body weight and food consumption were measured regularly
throughout the study. Complete gross postmortem examinations were
conducted on all animals and microscopic examinations were performed
on selected tissues from all animals.
The high-dose males exhibited a higher incidence of mortality
than controls during the first 14 months of the study. Mortality data
in the other treated groups were comparable to controls. The mean body
weights of the high-dose males and females were reduced throughout the
study and were statistically significant in high-dose males during the
first year, and in high-dose females for the first 18 months. Food
consumption was variable in control and treated groups.
Gross postmortem examinations revealed an increased incidence of
lesions of the small intestine (masses, nodules, raised areas) in
female mice fed 800 and 6 000 ppm of Captan. Microscopic examination
demonstrated an increased incidence of duodenal hyperplastic lesions
in high-dose male and female mice. The number of benign and malignant
duodenal neoplasias were significantly increased in high-dose females
only. Although the incidence in low- and high-dose males was
increased, it was not statistically significant. The incidence of
adenoma and carcinoma in the stomach, duodenum, and jejunum-ileum for
males was 0/100, 6/100, 1/100, 1/100 and 5/100; for females 0/100,
1/100, 3/100, 3/100 and 7/100 for 0, 100, 400, 800 and 6 000 ppm
groups, respectively. Historic control data derived from concurrent
studies in CD-1 mice indicate that 1/718 males developed a duodenal
carcinoma, with 0/737 incidence in females (Daly & Knezevick, 1983).
Groups of 30-day-old Charles River CD rats (70 males and 70
females per group) were administered Captan (89 percent purity) in the
diet at dose levels of 0, 25, 100 and 250 mg/kg bw/day for two years.
Animals were observed twice daily for signs of acute toxicity,
moribundity and mortality. Individual body weights were regularly
determined and food and compound consumption were measured.
Ophthalmoscopic, haematologic and clinical biochemical measurements
and urinalysis were performed periodically throughout the study. There
were no compound-related effects on any of these parameters. The mean
body weights for males and females given 100 and 250 mg/kg/day were
significantly lower than controls throughout the study.
Macroscopic examination at necropsy did not indicate any
significant differences between treated and control animals.
Microscopically, hepatocellular hypertrophy was significantly
increased in high-dose animals only, compared to controls. Male rats
demonstrated a statistically significant trend for kidney adenomas
(Krus-Kall Wallis test for adjusted trend, p<0.05; Armitage trend
test p<0.05). The incidence of kidney adenomas in males was 1/70,
1/70, 3/70 and 4/70 for control, 25, 100 and 250 mg/kg groups,
respectively. Although a significant trend is established, the
occurrence in the mid- and high-dose groups were not biologically
significant in light of the finding of this rare tumour in a control
Captan was without demonstrated adverse effects in CD rats when
administered in the diet for two years at 25 mg/kg bw/day (Goldenthal,
Captan was last considered by the 1982 JMPR.
An additional study has confirmed the lack of oncogenicity of
Captan in the CD rat. The ability of relatively high doses of Captan
to cause duodenal adenocarcinoma in CD-1 mice has also been confirmed.
However, duodenal neoplasia occurs in some controls.
Data from an additional single generation reproduction study
complemented and extended earlier data, establishing that Captan does
not adversely affect reproduction of CD rats at 12.5 mg/kg bw/day. The
meeting determined that there was no further concern with IBT studies,
as these had not been replaced with validated studies. An ADI was
Level Causing no Toxicological Effect
Monkey (rhesus, based on reproduction studies):
12.5 mg/kg bw/day.
Rat (based on reproduction studies):
250 ppm in the diet equal to 12.5 mg/kg bw.
Mouse: 800 ppm in the diet, equivalent to 120 mg/kg bw.
Dog: 100 mg/kg bw/day.
Estimate of Acceptable Daily Intake for Humans
0 - 0.1 mg/kg bw.
FURTHER WORK OR INFORMATION
Comparative study of the metabolic fate of Captan in rats and
Study of the pathogenesis of gastrointestinal lesions produced by
Captan in mice (known to be in progress).
Further observations in humans.
Aldrige, D., Shardein, J.L. & Blair, M. One-generation reproduction
1982 study in rats with Captan. International Research and
Development Corporation, USA. Submitted by Stauffer Chemical
Company, USA, to WHO. (Unpublished)
Bradfield, L.C., Wong, T.A. & MacGregor, J.A. Lifetime oncogenic
1981 feeding study of Captan Technical in CD-1 mice (ICR
derived). Chevron Environmental Health Center, Environmental
Health and Toxicology. Submitted by Chevron Chemical
Company, Richmond, CA, to WHO. (Unpublished)
Daly, I.W. & Knezevick, A.L. A lifetime oral oncogenicity study of
1983 Captan in mice. Bio/dynamics Inc. Submitted by Chevron
Chemical Company to WHO. (Unpublished)
Goldenthal, E. Two-year oral toxicity/carcinogenicity study of Captan
1982 in rats. International Research and Development Corporation.
Submitted by Stauffer Chemical Company, USA, to WHO.
Shardein, J.L. Teratology studying hamsters; amended final report.
1983 International Research and Development Corporation, USA.
Submitted by Chevron Chemical Company, Richmond, CA, to WHO.