PESTICIDE RESIDUES IN FOOD - 1983
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
Geneva, 5 - 14 December 1983
Food and Agriculture Organization of the United Nations
The 1977 JMPR was unable to establish an acceptable daily intake
(ADI) for daminozide owing to a lack of an adequate long-term rat
study and of information on the bio-transformation in animals. The
teratogenicity study reviewed by that Meeting was conducted by
Industrial Bio-Test Laboratories (IBT) and has been found invalid
Special Study on Teratogenicity
Daminozide (99 percent pure) was administered daily by gavage at
doses of 0, 300, 600 and 1 000 mg/kg to female Wistar rats from day 6
to 15 of gestation. On day 22 the dams were sacrificed and uterine
contents were removed and examined before necropsy. No signs of
toxicity were observed. Pregnancy rates, numbers of corpora lutea,
implantation and resorption rates, foetal deaths, sex ratio, foetal
weights and number of live foetuses were not significantly different
from control values. Neither the number of foetal anomalies nor the
incidence of gross skeletal malformations was found to be
significantly increased. Unfortunately, individual animal data were
not reported (Khera et al. 1979).
Special Studies on Carcinogenicity
Daminozide was administered from six weeks of age over the life
span of Swiss albino mice as a 2 percent solution in the drinking
water. Daily intake averaged 134 mg for males and 170 mg for females,
equivalent to 6.7 g/kg/day and 8.5 g/kg/day, respectively. Groups of
100 mice of either sex served as controls. The treatment significantly
shortened survival times compared with untreated controls. Significant
increases in the incidences of vascular, pulmonary and renal tumours
were reported. The incidence of vascular neoplasms, principally
hepatic angiosarcomas and angiomas, was reportedly increased from 8
percent (controls) to 72 percent in treated females and from 5 percent
to 74 percent in treated males. Similar increases in lung tumours,
adenomas and adenosarcomas occurred in treated females (74 percent)
1 See Annex 2 for FAO and WHO documentation.
and treated males (72 percent) compared to untreated controls (15
percent and 22 percent, respectively). In addition, 10 percent of
treated males developed benign renal adenomas; none were reported in
the controls. Further evaluation of this study was not possible as
individual animal data was not reported (Toth et al. 1977).
Groups of 50 male and 50 female Charles River B6C3F1 mice
received daminozide for 104 weeks at 5 000 and 10 000 ppm in the diet,
equivalent to 750 and 1 500 mg/kg/day. Twenty animals of either sex
were used as controls. The animals were observed for a further week
before sacrifice. The mean body weights of high-dose female mice were
lower than those of the controls throughout the bioassay. However,
mouse mortality was unaffected by daminozide treatment. Male mice
exhibited a dose-related increase in hepatocellular carcinomas, which
were significantly higher than controls at 10 000 ppm. However, the
high incidence of these tumours in historical controls obscures the
possible association of hepatocellular carcinomas with daminozide
treatment. Furthermore, this trend was not observed in female mice.
The incidence of alveolar or bronchiolar adenomas and carcinomas in
treated males was not significantly higher than for the matched
controls (NCI 1978).
Groups of 50 male and 50 female Fischer 344 rats were
administered daminozide for 104 weeks at 5 000 and 10 000 ppm in the
diet, equivalent to 250 and 500 mg/kg/day.
Twenty rats of either sex served as controls. The animals were
observed for a further week before sacrifice. Towards the end of the
study, the mean body weight of the higher-dosed rats was slightly
depressed. However, overall rat survival was not adversely affected by
treatment, although male rats had a higher mortality from week 66 to
the end of the study. Treated male rats exhibited a higher incidence
of interstitial testicular cell tumours than controls. These tumours
occur spontaneously at a high incidence in historical controls.
Treated female rats had small numbers of endometrial adenocarcinomas
and uterine leiomyosarcomas. Although these tumours were not present
in the relatively smaller number of controls, the incidence was too
low to be statistically significant. Nevertheless, the incidences of
these tumours were higher than expected from historical control data
Daminozide was reviewed by the 1977 Meeting but an ADI was not
estimated. The rat teratogenicity study reviewed at that time was
carried out by IBT and is invalid. A study subsequently published is
inadequate for the evaluation of teratogenicity. Consequently, the
Meeting deferred further consideration of this compound.
FURTHER WORK OR INFORMATION
Required (before an ADI can be estimated)
1. Adequate data to assess the carcinogenicity of daminozide.
2. An adequate teratogenicity study.
3. Information on biotransformation in animals.
REFERENCES - TOXICOLOGY
Khera, K.S., Whalen, C., Trivett, G. & Anyers, G. Teratologic
1979 assessment of maleic hydrazide and daminozide, and
formulations of ethoxyquin, thiabendazole and naled in rats.
J. Environ. Sci. Health, B14(6): 1563-77.
NCI. Bioassay of daminozide for possible carcinogenicity. CAS No.
1978 1596-84-5. US National Cancer Institute, Bethesda, Md. PB-
Toth, B., Wallcave, L., Patil, L., Schmeltz, I. & Hoffman, D.
1977 Induction of tumours in mice with the herbicide succinic
acid 2,2-dimethylhydrazide. Cancer Res., 37: 3497-3500.