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
PHORATE
C2H5O S
\ "
P - S - CH2SC2H5
/
C2H5O
Explanation
This compound was evaluated by the 1977 (FAO/WHO 1978)1 Joint
Meeting, but no ADI was allocated primarily due to the absence of
long-term studies. Further studies were required by the previous
Meeting to evaluate carcinogenic potential, teratogenic potential,
potential neurotoxicity and toxicity of metabolites. Observations in
humans were considered desirable. Some of the required studies have
been submitted and are reviewed in this monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
TOXICOLOGICAL STUDIES
Special Study on Teratogenicity
Rat
Groups of 25 mated female rats (CRL:COBS CD (SD)BR) were
intubated with technical phorate (purity not given) at 0, 0.125, 0.25
or 0.5 mg/kg bw/day on gestation days 6 through 15 (day 0 = day
copulatory plug present). The dams were sacrificed on day 20 of
gestation and the foetuses were removed for gross, skeletal and
visceral examination. Pregnancy rate was comparable in all groups.
During the gestation period, 7/23 and 1/24 pregnant dams,
respectively, at 0.5 mg/kg bw/day and 0.125 mg/kg bw/day died. An
increased frequency of foetuses at 0.5 mg/kg bw/day was found to have
enlarged heart. Other parameters evaluated, i.e. clinical signs, body
weight and food consumption of dams during gestation, number of
implantation sites, number of resorptions, number of dead foetuses,
mean live litter size, average foetal weight, sex ratio, gross,
skeletal and visceral abnormalities of foetuses, were not
significantly different from those in the controls. The teratogenic
"no effect" appeared to be 0.25 mg/kg bw (Litton 1978).
Groups of pregnant Sprague-Dawley rats (15 controls and 10
animals/treated group) were exposed (nose-only) in an inhalation
1 See Annex 2 for WHO and FAO documentation.
chamber to aerosols (with a count median diameter of 0.57 µm) of
technical phorate (78-90% pure) generated from a 1% solution of
phorate in xylene 1 hour/day from day 7 through 14 of gestation at
concentrations of 0.15 ± 0.04, 0.4 ± 0.15 or 1.94 ± 0.48 mg/m3. Three
groups of dams were used, respectively, as xylene controls, air
controls and restricted food controls. (The reason for including the
last group in the study was not specified.) All dams were sacrificed
on the 20th day of gestation and foetuses were removed by caesarean
section for visceral and skeletal examination. Five dams at the top
dosage group died and toxic signs (tremors, lacrimation and
exophthalmus) were noted in animals of this level. The entire litter
was resorbed in one of the dead dams. Based on summary data available,
there appeared to be no compound-related effects on body weight and
food consumption of dams during gestation, pregnancy rate, average
number of implants, average foetal weight, average number of sternal
ossification centres and incidence of supernumerary ribs. Average
foetal mortality (%) was markedly increased in the top dosage level.
No specific information was available on the incidence of any gross or
soft tissue abnormalities observed (Newell and Dilley 1978).
Special Studies on Carcinogenicity
(See also under Long-Term Studies).
Mouse
Groups of 41-day old mice (CD-1 strain, outbreed Swiss Albino, 50
males and 50 females/group) were fed technical phorate (85.5% pure) in
their diet at 0, 1, 3 or 6 ppm for 18 months. All animals dying or
sacrificed in moribund condition during the study or sacrificed
terminally, were subjected to gross and histopathological examination.
Survival was not adversely affected with 78-90% males and 66-74%
females of control and treated groups being still alive terminally.
Growth retardation was seen in females at 6 ppm practically throughout
the experiment. Animals of all treated groups appeared to consume less
food during the first 3 weeks and occasionally thereafter, but a
consistent dose-response relationship was not evident. Some clinical
signs, such as tremors, hyperactivity and excessive salivation, seemed
to occur at higher incidence and more frequently in animals of top
dosage group than in controls. Gross pathological findings were not
significantly different from those in the controls. Microscopic
evaluation of a wide range of tissues from each animal revealed no
alterations related to inclusion of phorate in the diet. Analysis of
tumour data indicated no significant dose-related increase in
incidence of any particular type of tumours, animals with tumours,
animals with malignant tumours and animals with multiple primary
tumours. Although incidence of alveolar/bronchiolar adenoma appeared
to be increased in males at 6 ppm (8/50 vs 3/50 controls) this was not
believed to be treatment-related since the increase was not
statistically significant, and the particular tumour is known to occur
frequently in control CD-1 mice. Under the conditions of the
experiment, phorate was not carcinogenic in the mouse (Litton 1981a).
Acute Toxicity
The acute toxicity of phorate in the rat is summarized in Table 1
and of phorate and its metabolite in the rat and mouse in Table 2.
Table 1. Acute Toxicity of Technical Phorate in Adult
Sprague-Dawley Rats 1
Route Sex LD50 (mg/kg bw) or LC50 (mg/m3)
Oral M 3.7
F 1.4
Intravenous M 2.2
F 1.2
Dermal M 9.3
F 3.9
Inhalation M 60
(1-hour exposure) F 11
1 Vehicle of administration was propylene glycol for the oral,
intravenous and dermal studies. The aerosols were generated from a 1%
solution of phorate in xylene. Duration of dermal exposure was not
specified, Source: Newell and Dilley 1978.
Table 2. Acute Toxicity of Phorate and Metabolites of Phorate 1
LD50 (mg/kg body weight)
Compound Rat Mouse
Oral Dermal Oral i.p.
Phorate 1.9-10 3 11 3
Phorate sulphoxide 2 - 4 11 7 1
Phorate sulphone 1.8-2 27 9 2
Phoratoxon 0.6-0.8
Phoratoxon sulphoxide 1.4-1.6 1 3 0.02
Phoratoxon sulphone 0.6-0.8 1.8 5 0.4
1 No information was available on strain and sex of animals or
other details of the studies such as vehicle of administration,
duration of dermal exposure, etc. Source; Blinn 1982.
Short-Term Studies
Rat
Groups of rats (Charles River CD strain, 51 days of age, 50 males
and 50 female controls, 30 male and 30 females /treated group) were
fed phorate sulphone (92% pure also containing 6% unchanged phorate
and about 2% of the sulphoxide derivative) in their diet at 0, 0.32,
0.8 or 2 ppm for 90 days. No mortality occurred. There were no
compound-related changes in appearance and behavior. Weight gain
appeared to be increased in males at both 0.8 and 2 ppm, together with
an increase in food consumption. Assay of tissue cholinesterase five
times over the course of the experiment indicated inhibition (20%) of
erythrocyte cholinesterase at 2 ppm (both sexes) at most time
intervals. Plasma cholinesterase was reduced at 2 ppm by 23-27% in
males after 1, 3 and 5 weeks and by 25-72% in females after all
sampling intervals. Inhibition (39%) of plasma cholinesterase also
occurred in females at 0.8 ppm after 1 and 3 weeks. Activity of brain
cholinesterase was reduced (20%) only in females at 2 ppm after 3, 5
and 8 weeks. There were no significant differences between control and
treated groups in values of hematocrit, haemoglobin and total white
blood count determined terminally. At the conclusion of the study, no
compound-related effects were observed with respect to absolute weight
of kidney and liver and gross pathological changes. Histopathological
evaluation of a variety of tissues from 5 males and 5 females of the
control and top dosage groups revealed no morphological alterations
attributable to treatment. The data suggested 0.32 ppm as a no-effect
level for the study (Hutchison et al 1968).
Long-Term Studies
Rat
Groups of 50 male and 50 female 5-week-old rats (CRL: COBS CD(SD)
BR) were fed dietary levels of technical phorate (84.5% pure) at 0, 1,
3 or 6 ppm for 24 months to evaluate the chronic toxicity and
potential carcinogenicity of the compound. Mortality appeared to be
increased in females at 6 ppm and only 36% of animals in this group
survived terminally. However, over 60% animals in all groups,
including the control, lived at least 90 weeks. The only compound-
related clinical signs observed in the treated groups were tremors
following over-dosing (327% of all the intended dosage levels) during
week 9. Growth was depressed in females at 6 ppm during the first 26
weeks and again between weeks 74 and 102. Food consumption was not
consistently affected in any dose-response pattern. Haematology,
clinical chemistry and urinalysis performed at 6, 12 and 24 months
indicated the only notable findings to be a decrease in erythrocyte,
haemoglobin and haematocrit values in females of the top dosage group
at 12 months. Dose-related inhibition (20%) of plasma cholinesterase
was noted in males at 6 ppm at 12 months, in males of all treated
groups at 24 months and in females at both 3 and 6 ppm at all sampling
intervals (3,6,12 and 24 months). Erythrocyte cholinesterase was not
significantly depressed (<20%) at any of the time intervals. Activity
of terminal brain cholinesterase was reduced (>20%) in males at 6 ppm
and in females at and above 3 ppm. At termination, females of top
dosage group showed an increase in organ/body weight ratio of adrenal,
brain, heart, liver and spleen. Gross pathological examination and
histopathological evaluation of a variety of tissues including the
aforementioned organs revealed the only apparent treatment-related
effect to be a significant increase at 6 ppm (both sexes but
particularly in males) in incidence of inflammation and epithelial
hyperplasia of the forestomach. Tumour data indicated the most
prevalent types of spontaneous tumours to be pituitary adenoma in both
sexes and mammary tumours in females. There was no significant
difference between control and treated groups in incidence, type and
time of detection of tumours. The study demonstrated 1 ppm as a
marginal no-effect level (Litton 1981b).
COMMENTS
In the available rat teratology study, phorate was found to be
non-teratogenic at oral doses up to 0.25 mg/kg bw. A 90-day feeding
study in rats with phorate sulphone indicated that this metabolite is
more potent that the parent compound as an inhibitor of
cholinesterases. Long-term studies in mice and rats revealed no
carcinogenic activity. Additionally, the long-term study in rats
indicated 1 ppm as a marginal no-effect level, with plasma
cholinesterase being the most sensitive index of biological activity.
No-effect levels have been established in rats and dogs. However,
in view of the continued unavailability of studies to evaluate
potentially delayed neurotoxicity, only a temporary ADI was allocated.
TOXICOLOGICAL EVALUATION
Level Causing no Toxicological Effect
Rat : 1 ppm in the diet equivalent to 0.05 mg/kg bw
Dog : 0.01 mg/kg bw
Estimate of Temporary Acceptable Daily Intake for Man
0 - 0.0002 mg/kg bw
FURTHER WORK OR INFORMATION
Required (by 1983)
An appropriate delayed neurotoxicity study.
Desirable
Observations in humans.
REFERENCES
Blinn, R.C. Personal communication to the World Health Organization by
1982 American Cyanamid Co.
Hutchison, E.B., Fegle, H.C., McNerney, J.M. and Levinskas, G.J.
1978 Report on sulphone of ThimetR systemic insecticide:ninety-
day repeated feeding to albino rats(CL 18,161). Report from
Central Medical Department, American Cyanamid Co. submitted
to the World Health Organization by American Cyanamid Co.
(Unpublished)
Litton. Teratology study in rats. ThimetRphorate. Final report from
1978 Litton Bionetics, Inc. submitted to the World Health
Organization by American Cyanamid Co. (Unpublished)
1981a 18-month chronic toxicity and potential carcinogenicity
study in mice. Phorate. Final report from Litton Bionetics,
Inc., submitted to the World Health Organization by American
Cyanamid Co. (Unpublished)
Litton. 24-month chronic toxicity and potential carcinogenicity study
1981b in rats. Phorate. Final report from Litton Bionetics, Inc.,
submitted to the World Health Organization by American
Cyanamid Co. (Unpublished)
Newell, G.W. and Dilley, J.V. Teratology and acute toxicology of
1978 selected chemical pesticides administered by inhalation.
U.S. E.P.A. Report No. 600/1-78-003, January 1978 submitted
to the World Health Organization by American Cyanamid Co.
See Also:
Toxicological Abbreviations
Phorate (ICSC)
Phorate (Pesticide residues in food: 1977 evaluations)
Phorate (Pesticide residues in food: 1984 evaluations)
Phorate (Pesticide residues in food: 1985 evaluations Part II Toxicology)
Phorate (Pesticide residues in food: 1994 evaluations Part II Toxicology)
Phorate (Pesticide residues in food: 1996 evaluations Part II Toxicological)