PESTICIDE RESIDUES IN FOOD - 1982
Sponsored jointly by FAO and WHO
EVALUATIONS 1982
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, 23 November - 2 December 1982
Food and Agriculture Organization of the United Nations
Rome 1983
PHOSPHAMIDON
CH3O O CH3 O C2H5
\" ' " /
P - O - C = C - C - N
/ ' \
CH3O Cl C2H5
Explanation
This pesticide was evaluated toxicologically at the Joint
Meetings in 1965, 1966, 1968 (FAO/WHO 1965, 1967, 1969)1, and an ADI
was established at the 1966 Meeting on the basis of no-effect levels
taken exclusively from data reported by Industrial Bio-Test
Laboratories (IBT). Additional data have become available and are
summarized and discussed in this monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
TOXICOLOGICAL STUDIES
Special Studies on Carcinogenicity
Mouse
Groups of 5-week old B6C3F1 mice (10 male and 10 female controls,
50 males and 50 females/treated group) were fed dietary levels of
technical phosphamidon at 0, 80 or 160 ppm for 62 weeks (160 ppm-
group) or 71 weeks (80 ppm-group) in males and 80 weeks in females
(both treated groups). The male animals were then placed on control
diet for 28 weeks (160 ppm-group) or 19 weeks (80 ppm-group) and
female animals, 11 weeks (both treated groups). Pooled controls,
consisting of 85 male and 85 female control mice from similar
bioassays of 8 other chemicals and the 10 male and 10 female controls
concurrent to the present study were used for statistical comparison.
Moribund animals and terminal survivors at 91 or 92 weeks were
sacrificed for necropsy and microscopic examination of major tissues
and all gross lesions. Necropsies were also conducted on all animals
found dead.
There was no compound-related effect on mortality. Between 84-92%
treated males and females, 70% control males and 100% control females
survived to termination. Generalized tremors, rough hair coats and poor
physical condition were seen in some males of both treated groups
after 60 weeks. Dose-related growth depression was apparent in males
at both 80 and 160 ppm practically throughout the study. Treated
1 See Annex 2 for WHO and FAO documentation.
animals exhibited no non-neoplastic lesions that could be associated
with the compound. Tumour data indicate no significant difference
between control and treated groups in incidence of any particular type
of tumour. Under the conditions of the experiment, there was no
indication of carcinogenicity of phosphamidon in B6C3F1 mice (NCI
1979).
Rat
Groups of 5-week old Osborne-Mendel rats (10 male and 10 female
controls, 50 males and 50 females/treated group) were fed technical
phosphamidon in their diet at 0, 80 or 160 ppm for 80 weeks and then
maintained on control diet for additional 30 weeks (males) or 31 weeks
(females). For statistical comparison, pooled controls were used,
which consisted of 85 male and 85 female controls from similar
bioassays of 8 other chemicals and the 10 male and 10 female controls
from the current study on phosphamidon. Moribund animals and terminal
survivors at 110 or 111 weeks were sacrificed for necropsy and
microscopic examination of major tissues and all gross lesions.
Necropsies were also conducted on all animals found dead.
Survival was not affected by treatment. Between 50 to 72% males
and 78 to 90% females of all groups, including the controls, survived
to the end of the experiment. Growth was depressed in both sexes at
160 ppm for most of the study. Hyperexcitability and tremors were seen
in some animals in both treated groups between weeks 6 and 16.
Histopathologically, except for a seeming increase at 160 ppm in
incidence of focal cellular changes in the liver and follicular cell
hyperplasia of the thyroid in males, there were no non-neoplastic
lesions attributable to the compound. A variety of tumours were
detected in the treated animals. Such neoplasms, either not dose-
related or comparable to controls in incidences, were likely to be
spontaneous in nature. However, tumours of the spleen and thyroid
seemed to occur more frequently in treated groups than in controls at
incidences as reported in Table 1.
It was indicated in the report that statistical analyses showed a
significant increase in combined incidence of spleen haemangioma and
haemangiosarcoma at 160 ppm and a significant dose-related trend with
respect to the combined incidence of splenic tumours in male rats when
compared to pooled controls. The comparison with concurrent controls
was not significant. Background incidence in the testing laboratory of
such splenic tumours in untreated male Osborne-Mendel rats was
reported as 6/240(3%), with incidences in individual groups as high as
3/9 (33%) and 2/9 (22%). No tumours of the spleen occurred in
females of the current study. As for thyroid tumours, there was a
statistically significant dose-related trend for the combined
incidence of C-cell adenoma and carcinoma in female rats when compared
to pooled controls. Incidences of these tumours in the female treated
groups were also significantly higher than in the pooled controls.
Table 1. Tumour Incidence in Rats Treated with Phosphamidon
Males Females
0 80ppm 160 ppm 0 80ppm 160 ppm
Spleen
Haemangioma 1/50(2)
Haemangiosaracoma 1/7(14)1 2/50(4) 5/49(10)
Haemartoma 1/50(2)
Thyroid
Follicular cell carcinoma 1/47(2) 0/10 1/50(2)
C-cell adenoma 7/48(15) 5/47(11) 0/10 8/50(16) 7/46(15)
C-cell carcinoma 1/8(13) 0/10 1/50(2) 1/46(2)
1 The numerator denotes the number of animals with the lesion and the denominator the number of animals with
the specific tissue examined microscopially. Figure in parentheses indicates incidence in %.
However, according to the historical records of the testing
laboratory, incidence of the particular thyroid tumours in untreated
females of Osborne-Mendel strain was 16/235(7%), with incidences in
individual control groups as high as 3/9(33%) and 3/10 (30%). In males
the incidence of thyroid tumours was not statistically significant.
The conclusion was made that "the data obtained in this bioassay with
Osborne-Mendel rats are insufficient to allow the interpretation that
technical-grade phosphamidon is carcinogenic in this species".
Following a review of the report on the current carcinogenic study of
phosphamidon, members of the Data Evaluation/Risk Assessment Subgroup
of the Clearinghouse on Environmental Carcinogens in the United States
were of the opinion that "the results from the assay should be
considered to be equivocal and, therefore, no conclusion drawn on the
carcinogenicity of phosphamidon" (NCI 1979).
COMMENTS
Phosphamidon was last reviewed by the 1968 JMPR. Additional data
now available included two carcinogenicity studies in rodents, one of
which (mice) was negative, and the other (rat) was inconclusive. It
was noted that no data on delayed neurotoxic potential had ever been
submitted.
An ADI was established at the 1966 Meeting on the basis of the
no-effect levels taken exclusively from IBT data, which have been
found to be invalid. The Meeting was informed that a number of
essential replacement studies had been commissioned. The Meeting
decided to change the ADI to a temporary status and requested that the
studies be submitted at the earliest possible date.
TOXICOLOGICAL EVALUATION
Level Causing no Toxicological Effect
Rat : 2 ppm in the diet, equivalent to 0.1 mg/kg bw
Dog : 0.5 mg/kg bw/day
Estimate of Temporary Acceptable Daily Intake for Man
0 - 0.001 mg/kg bw
FURTHER WORK OR INFORMATION
Required (by 1985)
1. The following replacement or new studies:
a. 2-year rat study;
b. 12-month dog study;
c. 2-generation reproduction study in rats;
d. Teratology studies in rats and rabbits;
e. Mutagenic studies.
2. An appropriate delayed neurotoxicity study.
Desirable
Further toxicity studies on the metabolites of phosphamidon.
REFERENCES
NCI Bioassay of phosphamidon for possible carcinogenicity, National
1979 Cancer Institute, Carcinogenesis Technical Report Series No.
16, D.H.E.W. Publication No.(NIH)79-816. Report of a study
performed at Gulf South Research Institute, Louisiana and
prepared at Tracor Jitco, Inc., under the direction of NCI.