PESTICIDE RESIDUES IN FOOD - 1984
Sponsored jointly by FAO and WHO
EVALUATIONS 1984
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
Rome, 24 September - 3 October 1984
Food and Agriculture Organization of the United Nations
Rome 1985
OXAMYL
Explanation
Oxamyl was first evaluated by the Joint Meeting in 1980 1/ and a
temporary ADI was estimated to be 0-0.01 mg/kg body weight. Additional
data were submitted in 1983 to the JMPR, but were received too late to
be evaluated fully. The temporary ADI was extended pending evaluation
of these data and clarification of the no-effect level in the rat.
Data on oxamyl and the dimethylcyanoformamide (DMCF) metabolite
requested by previous joint meetings are reviewed in this monograph
addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Metabolism
Twenty male mice (Swiss - Webster) received a dosage of
oxamyl-1-14C injected intraperitoneally, equivalent to 1.16 mg/kg
body weight. Pooled urine and faecal samples were collected from
groups of five mice at 6, 12, 24, 48, 72 and 96 h after dosing. At
96 h, all mice were killed and blood and other selected tissues were
analysed. Within 6 h, 72.7 percent and 3.0 percent of the dose were
excreted in the urine and faeces respectively, and 88.7 percent and
7.7 percent by 96 h. Parent oxamyl-14C accounted for approximately
15.5 percent of the organosoluble residue, and DMTO (43 percent) and
DMOA (20 percent) were the major metabolic forms found in urine.
Generally, tissue residues were low, ranging from 11 ng/g in testes to
37 ng/g in liver, identified only as oxamyl-14C equivalents. Results
from these analyses in mice support previous metabolism studies in
rats (Chang & Knowles, 1979).
Additional information concerning the identification of animal
tissue residues in rats indicated that 14C residues in tissues
(i.e. hair and skin) were actually derived from metabolic breakdown of
oxamyl and subsequently reincorporated into natural products, e.g.
amino acids. Ethyl extraction, including acid hydrolysis, of these
tissues failed to remove any radioactivity, demonstrating the absence
of oxamyl, oxamyl oxime, mono-methyl derivatives, DMCF or conjugates
of these derivatives. Further clarification or identification of these
fragments is unnecessary.
1/ See Annex 2 for FAO and WHO documentation.
TOXICOLOGICAL STUDIES
Special Study on Teratogenicity
Rabbit
Groups of rabbits (17 New Zealand Albino Rabbits/group) were
administered oxamyl orally at dosages of 0, 1, 2 and 4 mg/kg body
weight from days 6 through 19 of gestation in a standard teratology
bioassay. On day 29 of gestation, all surviving dams were sacrificed
and foetuses delivered by Caesarean section.
There was no mortality attributed to oxamyl and no treatment-
related clinical observations were noted. There was a statistically
significant body weight decrease in the mid- and high-dose females
during the treatment period. However, these females demonstrated
comparable body weight gains to controls during the post-treatment
period (days 19 to 29). Food consumption was not significantly
different between control and treatment groups. Pregnancy rates
between treated and control groups were comparable (88 vs 100 percent
except in the high-dose group where marginal effects were observed (76
percent pregnant). The data related to reproduction (implantations,
corpora lutea and live young) were comparable, except for resorptions,
which were slightly increased in mid- and high-dose females. Foetal
viability was slightly reduced in the high-dose group. Crown-rump
measurements and mean foetal body weights were not affected by
treatment. Internal development, including somatic and skeletal
development, was comparable among all groups. There were no
teratogenic effects from the administration of oxamyl to pregnant
rabbits at doses up to and including 4 mg/kg bw during the critical
period of organogenesis. There were, however, faetotoxic effects at
the high dose (Hoberman et al., 1980).
Special Study on Carcinogenicity
Mouse
Groups of CD-1 mice (80/sex/group) were administered oxamyl (97.1
percent a.i.) in the diet at dose levels of 0, 25, 50 and 100 ppm for
two years. The 100 ppm dose was reduced to 75 ppm after six weeks
because of increased mortality. Additional animals were added from the
same shipment group. Animals were 4-1/2 to 5 weeks old at the start of
the study, except for the animals added. Mice were examined daily for
signs of mortality, toxicity and behavioral changes; weekly for
palpable masses; and regularly weighed for body weight changes. Food
consumption was similarly determined on a routine basis.
Haematological samples, taken from the orbital sinus, were analysed
periodically on ten male and ten female mice randomly selected from
each group. Selected organs weighed from all surviving animals
included: liver, kidneys, testes, brain and brain stem, and heart.
Gross necropsy was performed on all animals together with microscopic
examinations, which included a complete series of organs and tissues.
There was no long-term reduction in survival associated with the
ingestion of oxamyl, although initially (<6 weeks) high dose males
and mid- and high-dose females experienced high mortality rates. The
high dose was accordingly reduced from 100 to 75 ppm and replacement
animals added. Males demonstrated significant reductions in body
weight throughout the study at 50 ppm. Although 75 ppm male body
weights were significantly reduced during the first 28 weeks, they
were not consistently depressed for the remainder of the study.
Females demonstrated significant but sporadic body weight decreases at
50 and 75 ppm throughout the study. Food consumption for females was
equally sporadic, with no dose-related trends throughout the test.
Males, however, at 50 and 75 ppm showed a consistent pattern of
decreased food consumption throughout the study. Sporadic changes were
evident at 25 ppm for the first 28 weeks, but there were uniform
decreases in food consumption from weeks 38 to 84.
There were no apparent dose-related changes in the haematological
parameters, although significant decreases in RBC, HGB and HCT were
evidenced at four weeks for high dose males. These were not similarly
effected at other time points. Morphology of peripheral blood did not
identify any unusual cell types such as reticulocytes, spherocytes,
Howell-Jolly bodies, etc. These spurious results are not considered to
be related to treatment. Organ weights, both absolute and relative,
were not affected by treatment, except for a marginal increase in
kidney-to-body weight ratio for high dose males. Gross and
histopathological examinations revealed evidence of glomerulo
sclerosis and chronic interstitial nephritis among all groups,
including controls. There was no apparent compound-related effect for
this response and, therefore, the increase in kidney-to-body weight
ratio for high-dose males is probably related to the noted decrease in
body weight and not to a specific target organ effect. The occurrence
of benign lung adenomas in males was apparently inversely proportional
to dose. This trend was not evident in females, as low- and high-dose
groups had a higher incidence than controls, but there was no
measurable difference between control and mid-dose females. These
occurrences are considered fortuitous since the incidence is within
historical control data accumulated from five other studies from the
same laboratory conducted during the same time period (1978-81).
Oxamyl was not oncogenic in this strain of mouse at doses up to and
including 75 ppm. The NOEL was demonstrated at 25 ppm, based on body
weight depression (Adamik et al., 1981).
The available data concerning body weight depression in rats were
re-evaluated in order to clarify an apparent compound-related effect
at 50 ppm. The two-year rat feeding study and three-generation rat
reproduction study indicate that this effect is most noticeable in
males. Body weight effects in the reproduction study were not
statistically significant at 50 ppm, although slightly lower than
controls, whereas 100 and 150 ppm did provide measureable body weight
depression compared to controls. The data from the two-year rat
feeding study demonstrate that male body weights are depressed
initially, reach a plateau and remain 15-20 g less than controls for
the majority of the study. Weight gain for the 50 ppm males actually
exceeds controls at 12 months and remains greater than controls until
month 21. Apparently, during the early growth stages where dietary
intake versus body weight is increased, animals are receiving more
oxamyl on a mg/kg body weight basis. Such changes are evident until
the rats are 10 to 14 weeks old, when their food consumption and body
weight stabilize or reach a plateau. The body weight decrease was
reversed when rats reached this plateau in their normal growth curve
and food consumption vs body weight became stabilized. It would appear
that if rats had received the same amount in the diet on a mg/kg body
weight basis throughout their normal lifespan, no measureable
differences would be evident in body weight gain. Furthermore, this
level produced no measureable adverse effect on longevity, haemotology
or clinical chemistry and no pathological change was noted. Therefore,
on a mg/kg bw basis it would appear that 2.5 mg/kg bw is without
adverse effect on the body weight of rats.
Special Studies on Mutagenicity
Oxamyl was negative in a series of mutagenicity studies (see
Table 1).
COMMENTS
Oxamyl was assigned a temporary ADI in 1980 and additional data
and information were identified, which have been reviewed in this
addendum.
Metabolism studies in mice support previously reviewed studies;
73 percent of the dose (1.16 mg/kg ip) was excreted in urine within
six hours. Tissue residues were low, ranging from 11 ng/g (testes) to
37 ng/g (liver).
Information presented indicated that residues in skin and hair of
rats were derived from the metabolic breakdown of oxamyl. The absence
of toxicity indicates that identification of these fragments is
unnecessary.
A teratology study in rabbits provided no evidence of teratogenic
effects at doses up to and including 4 mg/kg body weight, although
faetotoxicity was indicated at this high dose.
Mutagenicity data were negative, as was a mouse oncogenicity
study. Reduced food consumption and decreased body weight gains were
evident at 50 and 75 ppm, but not at 25 ppm.
The available data concerning body weight depression, primarily
in rats, were re-evaluated to clarify an apparent compound-related
effect at 50 ppm. It was determined that oxamyl produced no adverse
effects on body weight gain at 2.5 mg/kg bw. Accordingly, the meeting
determined that sufficient toxicity data were available to estimate an
ADI.
TABLE 1. Special Studies on Mutagenicity
Test system Test organism Concentration Purity Results Reference
of oxamyl used
Ames Test S. typhimurium 50, 100, 500, 97.1% Negative Summers,
(both with TA 98 1000, 5000, and 1981
without TA 100 10,000 ug/plate
metabolic TA 1535
activation) TA 1537
In Vitro Chinese 1st trial non- 97.1% No evidence Galloway,
Cytogenetics Hamster activation: 2.3, of mutagenic 1982
Ovary Cells 7.0, 23.3, 70 or clastogenic
and 700 ug/ml potential
2nd trial non- due to
activation: 12.5, oxamyl.
25, 50, 75 and Positive response
100 ug/ml with mitomycin C
Activation: 2.3, and cyclophosphamide
7.0, 23.3, 70
233, and 700 ug/ml
Unscheduled Rat 1x10-5 1x10-4, 97.1% Negative. Summers,
DNA Repair hepatocytes 1x10-3', 1x10-2', Positive 1982a
Synthesis 0.1, 10mM oxamyl control
with gentamycin (1 mM DMBA)
(50 ug/ml) and gave expected
tritium labeled positive
thymidine (5 uCi/ response
ml).
TABLE 1. (continued)
Test system Test organism Concentration Purity Results Reference
of oxamyl used
Forward Chinese Nonactivation: 97.1% Oxamyl was Summers,
Mutation Hamster 50, 200, 500 and apparently 1982b
Ovary Cells 750 uM negative in
and Activation: both activated
Hypoxanthine- 25, 100, 300, and non-
guanine 500 and 700 uM activated
phosphoribosyl systems
transferase
TOXICOLOGICAL EVALUATION
Level Causing no Toxicological Effect
Dog: 100 ppm in the diet, equivalent to 2.5 mg/kg bw/day;
Rat: 50 ppm in the diet, equivalent to 2.5 mg/kg bw/day.
Estimate of Acceptable Daily Intake for Man
0-0.03 mg/kg bw
FURTHER WORK OR INFORMATION
Desirable: Observations in humans
REFERENCES
Adamik, E.R. et al. Long-term feeding study in mice with oxamyl.
1981 Project #WIL-77033; HLO-252-81 from Wil Research
Laboratories, Inc., submitted by E.I. DuPont de Nemours to
WHO. (Unpublished)
Chang, K-M & Knowles, C.O. Metabolism of oxamyl in mice and two-
1979 spotted spider mites. Arch. Environ. Contam. Toxicol.,
8:499-508.
Galloway, S.M. Mutagenicity evaluation of H14190 (oxamyl) in an in
1982 vitro cytogenetic assay measuring chromosome aberration
frequencies in Chinese hamster ovary (CHO) cells. Report
from Litton Bionetics, Inc. submitted by E.I. DuPont de
Nemours to WHO. (Unpublished)
Hoberman, A.M. et al. Teratology study in rabbits (Project #201-245;
1980 HLO-0801-80). Report from Hazleton Laboratories America,
Inc. submitted by E.I. DuPont de Nemours to WHO.
(Unpublished)
Summers, J.C. Mutagenicity evaluation in Salmonella typhimurium from
1981 Report No. 614-81 from Haskell Lab. submitted by E.I. DuPont
de Nemours to WHO.
Summers, J.C. Unscheduled DNA synthesis/rat hepatocytes in vitro.
1982a Report No. 719-82 from Haskell Lab. submitted by E.I. DuPont
de Nemours to WHO. (Unpublished)
Summers, J.C. Chinese Hamster Ovary cell assay for mutagenicity.
1982b Report No. 265-82 from Haskell Lab. submitted by E.I. DuPont
de Nemours to WHO. (Unpublished)