FAO, PL:CP/15
WHO/Food Add./67.32
EVALUATION OF SOME PESTICIDE RESIDUES IN FOOD
The content of this document is the result of the deliberations of the
Joint Meeting of the FAO Working Party and the WHO Expert Committee on
Pesticide Residues, which met in Geneva, 14-21 November 1966.1
1 Report of a Joint Meeting of the FAO Working Party and the WHO
Expert Committee on Pesticide Residues, FAO Agricultural Studies, in
press; Wld Hlth Org. techn. Rep. Ser., 1967, in press
PHOSPHAMIDON
(Addendum to 1965 Monograph)
This pesticide was evaluated by the Joint Meeting of the FAO committee
on Pesticides in Agriculture and the WHO Expert Committee on Pesticide
Residues in its 1965 report (FAO Meeting Report No. PL/1965/10/1;
WHO/Food Add./27.65). Since its publication some new experimental work
has been reported on the compound. This new work in presented and
discussed in the following monograph addendum.
BIOLOGICAL DATA AND TOXICOLOGICAL EVALUATION
Biochemical aspects
The alpha- and beta-isomer of desethylphosphamidon was isolated from
bean plants (Vicia faba) in the ratio 1:2 (CIBA, 1964a).
Acute toxicity
In acute oral toxicity studies in male albino rats, the toxicity of
phosphamidon was not potentiated when administered in combination with
azinphos-methyl, carbaryl, carbophenothion, demeton, diazinon,
dioxathion, EPN, ethion, malathion, methyl parathion, parathion,
mevinphos, naled and schradan (Kay & Calandra, 1961).
The oral LD50 in rats of desethylphosphamidon is: for beta-isomer,
8.5 mg/kg; for alpha-isomer, 250 mg/kg body-weight (CIBA, 1964a).
The oral LD50 of desmethylphosphamidon in male rats is 2500 + 420
mg/kg. The oral LD50 of gamma-chlorophosphamidon is 126 + 6.8
mg/kg in rats and 117 + 25 mg/kg in mice (CIBA, 1964b; Cervenka et
al., 1964).
In man a fatal case of oral poisoning and a probable case of mild
poisoning is described. In the fatal case, post-mortem examination
revealed a fatty liver, congestion of internal organs and brain damage
of the type seen in anoxia. The clinical picture in both cases
resembled that seen in poisoning with other organophosphates (Gitelson
at al., 1965).
Short-term studies
Rat. Groups of 5 male and 5 female rats were exposed to inhalation
of phosphamidon at concentrations of 0.05 and 0.5 mg/m3 or 4 hours a
day for 6 weeks. A temporary decrease of cholinesterase activity in
erythrocytes and in plasma was compensated after 2 weeks (CIBA, 1965).
Groups of 50 male and 50 female rats were fed diets containing 0, 1,
2, 3, 5 and 7.5 ppm phosphamidon for 12 weeks. The cholinesterase
activity was measured in plasma, erythrocytes and brain. No
significant inhibition of cholinesterase was found at the 2.0 ppm
dietary level. (Kay & Calandra, 1961).
Groups of 15 male and 15 female rats were fed phosphamidon in the diet
for 13 months. The doses were 0, 0.1, 0.5, 1.25 and 5.0 mg/kg
body-weight/day and were periodically compensated for change in
body-weight and food consumption. A significant decrease of growth and
depressed food intake was recorded only in the males fed 1.25 and 5.0
mg/kg/day. The other 2 groups (0.1 and 0.5 mg/kg/day) were comparable
with the control group. No difference in mortality, tumour incidence,
peripheral blood picture, urine, and gross and microscopic appearance
of tissues was seen between the groups. (Kohn et al., 1964).
A 3-generation reproduction study was performed in rats. Three groups
of 8 male and 16 female rats were fed 1.0, 7.5 and 15 ppm of a
phosphamidon mixture (75 per cent phosphamidon, 22 per cent
desethylphosphamidon, 3 per cent N,N-diethyl-a-chloroacetoacetamide)
in the diet. Two other groups served as controls. The rats were mated
at 74 and 105 days. The second litter served to produce 2 F2
generations. In all three generations, body weight and weight gain
were similar to those of the controls. No abnormal reaction was noted,
and none of the deaths in the course of the experiment was attributed
to the substance tested. Mating indices, fertility indices, incidence
of pregnancy, parturition and gestation times, body-weight and
histology were essentially comparable with control animals. Lactation
indices were slightly lower in the P and F2 groups fed the highest
dose (15 ppm). Litter survival was reduced at 15 ppm (Kennedy et al.,
1966).
Dog. Groups of 3 male and 3 female beagles were given phosphamidon
orally in capsules at dose levels of 0, 0.05, 0.1, 0.5, 1.0, 2.0, 3.0,
4.0 and 5.0 mg/kg body-weight/day. The doses of 0.05-1 mg/kg/day were
administered for 90 days. Plasma and erythrocyte cholinesterase
activity was determined by an electrometric method. At a dose of 1
mg/kg/day and higher significant inhibition of cholinesterase was
caused in 9-16 days. No depression of cholinesterase was observed at
dose levels of 0.5 mg/kg/day or lower within 90 days. (Kay & Calandra,
1961).
Four groups of dogs (2 males and 2 females in each group) were given
phosphamidon orally in gelatin capsules at dose levels of 0, 0.1, 2.5
and 5.0 mg/kg body-weight/day for 2 years. Body-weight and food
consumption, behavioural reactions and mortality were followed up, and
haematologic studies, blood urea nitrogen determination, urine
analyses including examinations for albumin, glucose and microscopic
elements and liver function tests were conducted. The test was
concluded by the determination of organ-weights together with their
histopathologic examination. The dogs in the highest dose group (5
mg/kg/day) perished in the course of the test, as a consequence of
phosphamidon ingestion. In the group receiving a dose of 2.5
mg/kg/day, slight muscular tremors were observed in females in the
first year of the test, and in the second year slight muscular tremors
appeared also in males, together with a slight salivation. At the
highest dose level, alterations in organ weights and ratios were
found. However, histologic examination revealed no alterations which
could have been caused by Phosphamidon. No degenerative changes were
noted in the myelin sheath. There were no significant effects detected
at a dose level of 0.1 mg/kg/day. (Cervenka et al., 1964).
Comments
In a 12-week experiment using rats, 2 ppm in the diet did not cause
any significant decrease of cholinesterase in the plasma, erythrocytes
and brain; in a 90-day test using dogs, 0.5 mg/kg/day did not result
in any inhibition in plasma and erythrocytes.
A mixture of phosphamidon and 2 of its metabolites had no effect on
the reproductive capacity of rats at a dietary level of 7.5 ppm,
equivalent to 0.37 mg/kg/day.
Biochemical and metabolic fate studies in man exposed to this compound
by different routes, reproduction studies in at least one more species
other than the rat, and short-term toxicity studies of metabolites and
break-down products of phosphamidon are desirable.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Rat ppm, equ. 0.1 mg/kg/day
Dog 0.5 mg/kg/day
Estimate of acceptable daily intake for man
0-0.001 mg/kg body-weight
REFERENCES
Cervenka, H., Kay, J. H. & Calandra, J. C. (1964) Unpublished report
submitted by CIBA.
CIBA (1964a) Unpublished report by R. Anliker & E. Kühl.
CIBA (1964b) Unpublished report by J. Tripod & R. Anliker
CIBA (1965) Unpublished report by Bericht von A. Hoffman & K. H.
Bergert (Batelle-Institut E.V.-Frankfurt am Main).
Gitelson, S., Davidson, J. T. & Werczberger, A. (1965) Brit. J.
industr. Med., 22, 236
Kay, J. H. & Calandra, J. C. (1964) Unpublished report submitted by
CIBA.
Kennedy, G., Fancher, O. E. & Calandra, J. C. (1966) Unpublished
report submitted by CIBA
Kohn, F. E., Kay, J. H. & Calandra, J. C. (1964) Unpublished report
submitted by CIBA
Palazzolo, R. J., Kay, J. H. & Calandra, J. C. (1964) Unpublished
report submitted by CIBA
See Also:
Toxicological Abbreviations
Phosphamidon (ICSC)
Phosphamidon (PIM 454)
Phosphamidon (FAO Meeting Report PL/1965/10/1)
Phosphamidon (FAO/PL:1968/M/9/1)
Phosphamidon (FAO/PL:1969/M/17/1)
Phosphamidon (WHO Pesticide Residues Series 2)
Phosphamidon (WHO Pesticide Residues Series 4)
Phosphamidon (Pesticide residues in food: 1982 evaluations)
Phosphamidon (Pesticide residues in food: 1986 evaluations Part II Toxicology)