PESTICIDE RESIDUES IN FOOD - 1981
Sponsored jointly by FAO and WHO
EVALUATIONS 1981
Food and Agriculture Organization of the United Nations
Rome
FAO PLANT PRODUCTION AND PROTECTION PAPER 42
pesticide residues in food:
1981 evaluations
the monographs
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, 23 November-2 December 1981
FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS
Rome 1982
CYHEXATIN
Explanation
This acaricide was evaluated by the FAO/WHO Joint Meeting in 1970
and 1978.* The estimate of the temporary acceptable daily intake for
man, set in 1970, was extended in 1973 and 1978.
In 1978 clarification of the no-effect level in the rat in order
to elucidate the significance of focal bile duct hyperplasia at low
dose levels was required by 1980. A study to elucidate the possible
effect on the immune system was desirable.
A further evaluation of the focal bile duct hyperplasia findings
is presented herewith. In addition, a report of life-time feeding
studies of cyhexatin to mice was available. Additional reports of
toxicological studies of dogs were submitted.
DATA FOR THE ESTIMATION OF ACCEPTABLE DAILY INTAKE
TOXICOLOGICAL STUDIES
Focal bile duct hyperplasia - rats
All of the liver slides prepared for microscopic examination from
rats of the dietary study with cyhexatin reported by S.D. Warner
et al (1977) were re-evaluated by Dr. van der Heijden, pathologist.
He clearly states that focal bile duct hyperplasia is a common finding
in livers of ageing rats of various strains and is of little
pathological significance. However, it appears likely that some
environmental factor, e.g. contaminants of food or deficiency, is
responsible for the frequently found high incidence. The occurrence
of focal bile duct hyperplasia in control and treated rats is
considered "spontaneous" and generally not associated with a
particular condition or treatment. There is no association between
focal bile duct hyperplasia and tumours of the liver or bile ducts and
no evidence to relate focal bile duct hyperplasia to any preneoplastic
condition (Van der Heijden 1980).
* See Annex II for FAO and WHO documentation.
Short-term studies
Mice
Groups of male and female B6C3F1 mice (10/sex/group) received
diets containing cyhexatin for 13 weeks in concentrations of about 0,
3, 6 or 10 mg/kg bw/day. Slight, not dose-related, decreases in food
consumption occurred during some periods in all treated groups of
females.
Cyhexatin did not induce dose-related effects on body weight,
organ weights including the heart, or gross and microscopic pathology.
At the end of the experiment, PCB-values were significantly increased
in the male animals of the highest dose level. The no-effect level in
this study is about 6 mg/kg bw (McCollister et al 1980).
Dog
Groups of 8 male beagle dogs were given oral doses of 0, 0.75,
1.50 or 6 mg cyhexatin/kg for 6 months. Treatment-related clinical
signs included intermittent loose stools, inappetence, increased
physical activity and rough hair. Loose stools were observed in all
treatment levels in a dose-response manner. After the test compound
was removed from the basal ration and given separately admixed in
canned food, food intake was increased, especially at the highest dose
level. Increased physical activity was first observed at the 6.0 mg/kg
bw dose level, and thereafter also at the 0.75 and 1.50 mg/kg levels.
Terminal physical examination did not indicate the presence of any
abnormality. In the highest dose groups, body weight and body
temperature were decreased. Cyhexatin did not have clear dose-related
effects on heart rate, blood pressure, ECG-recording, urinalysis or
clinical chemistry. At the end of the study, haematological values
(RBC, Hb and PCV) were decreased in the 6 mg/kg group. In all
experimental groups, the weight of the heart was not dose-relatedly
increased. No gross or microscopic alterations were observed that
could be related to the treatment (Gerbig and Warner 1975).
In order to study the increased physical activity as found in the
previous experiment, 3 groups of male beagle dogs received in their
diets 0, 0.4 to 0.75, and 0.4 to 1.5 mg cyhexatin/kg bw during 13
weeks. The daily activity of each dog was recorded by means of
actometers. The activity of dogs fed 1.5 mg/kg bw was clearly
depressed. No noticeable differences in physical activity occurred
between the 0.75 mg/kg group and the controls. The absolute heart
weight was not affected, whereas the relative weight was significantly
increased (Reuzel 1977).
Long-term studies
Mice
Groups of 60 male and 60 female B6C3F1 mice were maintained on
diets formulated to supply 0 (96 males and 96 females), 1, 3 or 6 mg
cyhexatin/kg bw for up to 2 years. After one year, 10 male and 10
female mice of each group were killed. In the highest dose level
mortality was increased in the males and decreased in the females. The
body weight gain in the males was lowered in comparison to controls,
whereas in both males and females the food intake was marginally
affected. No dose-related effects were observed on behaviour,
haematology, clinical chemistry, organ weights or tumour incidence. At
the highest dose level of 6 mg/kg bw/day, there were indications that
the incidence of a few of the normal changes may have been affected by
the treatment, e.g. a decrease in sinusoidal distension and/or
increased inflammatory or reticuloendothelial cell activity, a
decrease of uterine endometrial hyperplasia in the lymph nodes and a
decrease in adenoma formations in the pituitary. Biliary hyperplasia
or cyst formation occurred only in a few isolated cases. The no-effect
level is 3 mg/kg bw (Keyes et al 1981).
EVALUATION
COMMENTS
A six-month toxicity study in dogs has been received and
evaluated. A subjective observation of dose-related increased activity
was reported. A second study, measuring activity with an actometer,
failed to confirm this observation.
A statement from an independent pathologist indicated that the
local bile duct hyperplasia noted in an earlier JMPR evaluation is a
normal finding in ageing rats and may be considered to be of
negligible pathological significance. This statement was confirmed by
the Meeting.
Two mouse studies, one of 13 weeks and one lifetime study, were
evaluated. The lifetime study permitted the estimation of a no-effect
level of 3 mg/kg bw/day in this species.
The estimated temporary acceptable daily intake for man
(0.008 mg/kg bw) was based on the no-effect level (0.75 mg/kg) in
2-year dog feeding studies evaluated in 1970. The receipt of the long-
term study in rats and the additional studies in dogs justified the
alteration of the temporary ADI to a full ADI.
Level causing no toxicological effect
Mouse: 3 mg/kg bw/day
Rat: 1 mg/kg bw/day
Dog: 30 ppm in the diet, adjusted to give 0.75 mg/kg bw/day
Estimated acceptable daily intake for man
0 - 0.008 mg/kg bw
FURTHER WORK OR INFORMATION
Desirable
1. A study to elucidate the possible effect on the immune system.
2. A study to determine the possibility of CNS effects.
REFERENCES
Gerbig, G.G. and Warner, S.D. Results of a six month oral (dietary)
1975 toxicity study of tricyclohexyltin hydroxide in male beagle
dogs (Dow Chemical Company. (Unpublished)
McCollister, S.B. et al. Cyhexatin: Results of a 13-week toxicity
1980 study in the diet of B6C3F1 mice. Dow Chemical Company.
(Unpublished)
Keyes, D.G. et al. Cyhexatin: Results of a two-year dietary toxicity
1981 and oncogenic study in male and female B6C3F1 mice. Dow
Chemical Company. (Unpublished)
Reuzel, P.G.J. Sub-chronic (13-week) activity study with TCHT in
1977 beagle dogs. Report No. R5464. Central Institute for
Nutrition and Food Research, The Netherlands. (Unpublished)
Van der Heijden, C.A. Letter d.d. 7-8-1980, to Dow Chemical Europe
1980
Warner, S.D., Ayers, K.M., Gerbig, G.G. and Strebing, R.J. Results of
1977 a two-year chronic toxicity study of tricyclohexyltin
hydroxide administered to rats by the dietary route. Report
by Dow Chemical Company, U.S.A. (Unpublished)