Oxamyl was evaluated by the Joint Meetings in 1980 and 1984
(Annex 1, FAO/WHO, 1981a, 1985b). A toxicological monograph was
prepared by the Joint Meeting in 1980 (Annex 1, FAO/WHO, 1981b) and a
monograph addendum was prepared in 1984 (Annex 1, FAO/WHO, 1985c). A
full acceptable daily intake of 0-0.03 mg/kg b.w. was estimated in
1984. Data concerning the dimethylcyanoformamide (DMCF) metabolite
were inadvertently omitted from the 1984 monograph addendum; they were
evaluated by the 1985 Meeting and are included in this monograph
EVALUATION FOR ACCEPTABLE DAILY INTAKE
Special study on mutagenicity of DMCF
DMCF did not show any mutagenic potential when tested in an Ames
test with and without metabolic activation (Table 1).
Special study on acute toxicity of DMCF
A separate determination of the acute lethal dose (ALD) to rats
was estimated to be 450 mg/kg b.w. (Ashley, 1974).
Special study on subchronic toxicity of DMCF
Groups of ChR-CD rats (16 males and 16 females per group) were
administered DMCF (100% purity) in the diet at dose levels of 0, 50,
150, or 450 ppm for 90 days. All animals were observed for overt
toxicity and behavioural changes daily, while body weight and food
consumption were recorded weekly. Haematologic, clinical chemistry and
urinalysis determinations were performed on 10 rats/sex from the
control, intermediate and high-dose groups after 30, 60 and 90
continuous days of study. Blood samples were taken from the tail.
Gross pathological examinations were performed on surviving animals
(except animals used in a subsequent reproduction study). Ten rats per
sex in the control and high-dose groups were examined microscopically,
including target organs from animals in the other dose groups.
Table 1. Results of mutagenicity assays of DMCF
Test System Test Object Concentration Purity Results Reference
of DMCF Used
Ames Test S. typhimurium 250, 500, approx. 100% Negative. Summers,
(both with TA 98 1000, 2500, Positive 1978
and without TA 100 3000, 5000, responses
metabolic TA 1535 5000, 7000, with 2-AA,
activation) TA 1537 and 10,000 2-NF, MNNG
TA 1538 µg/plate and 9-AAc.
Results from the 90-day study demonstrated decreased food
consumption and body-weight gain at the high dose for both sexes. On a
mg/kg b.w./day basis, the average compound ingestion for 50-ppm males
and females was 4.0 and 4.2 mg/kg b.w., respectively; for 150-ppm
males and females it was 11.4 and 12.6 mg/kg b.w., respectively; and
for 450-ppm males and females it was 34.4 and 35.7 mg/kg b.w.
Hematological examinations demonstrated decreased red blood cells
(RBC), hemoglobin, hematocrit, white blood cells (WBC), and increased
eosinophils (%) in males and females given 450 ppm. At 150 ppm, RBC
and WBC were decreased in females only, and then only at the 90-day
interval. Urinalysis was unremarkable except for males and females
given 50 ppm, where both sexes had significantly-increased volumes;
however, the urine osmolality of males was increased, whereas the
urine osmolality of females decreased (these were 90-day analyses
only). Clinical chemistries (alkaline phosphatase, glutamate-pyruvate
transaminase (GPT), glutamate-oxaloacetate-transaminase (GOT), and
lactate dehydrogenase (LDH) were similar to controls except for an
apparent decreased LDH in females at all levels at the 90-day
interval. This is probably the result of a 2-fold increase in the
control females' LDH value at the same time interval and not a
compound-related effect. Males did not demonstrate the same response.
Organ-weight data were not reported, and gross and histopathology
were extremely limited (average 10 rats/sex/dose, limited information
on tissues reported). Examination of eyes from all groups demonstrated
an increased incidence in localized focus of retinal atrophy in
females at 150 and 450 ppm, compared to controls (0-1/10, 150-6/10,
450-4/10); and for males at 150 and 450 ppm (0-0/10, 150-3/10,
450-1/10). Although not increasing in a dose-related manner, the
occurence nonetheless appears to be a consequence of compound
ingestion. The incidence of hydronephrosis in males was also increased
over controls at 150 and 450 ppm (0-1/10, 150-6/10, 450-7/10). This
incidence was not similarly apparent in females, although females in
all groups demonstrated minute foci of mineralization (0-3/10,
50-6/10, 150-4/10, 450-9/9). These changes were indicated to be common
findings among ChR-CD rats; however, the incidence appears to increase
with dose, although not uniformly between sexes. Based on the limited
data reported, the effects on kidneys and eyes at > 150 ppm, and
the haematological effects noted at > 150 ppm, the no-observed-
effect level in this study is considered to be 50 ppm (equal to 4.0
and 4.2 mg/kg b.w. in males and females, respectively). Insufficient
data were presented on the reproductive evaluation of DMCF to permit
an evaluation (Willigan, 1977).
Information presented on the metabolite DMCF demonstrates
moderate toxicity in rats.
A subchronic 90-day feeding study in rats using DMCF demonstrated
no apparent compound-related effects at 50 ppm (equal to 4.0 and
4.2 mg/kg b.w. in males and females, respectively). Target organs
appeared to be kidneys and eyes, although limited data were presented.
A mutagenicity assay using the Salmonella typhimurium test
system was negative.
These do not alter previous evaluations for oxamyl, so the ADI
for oxamyl was reaffirmed.
LEVEL CAUSING NO TOXICOLOGICAL EFFECT
Dog: 100 ppm in the diet, equivalent to 2.5 mg/kg b.w.
Rat: 50 ppm in the diet, equivalent to 2.5 mg/kg b.w.
ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN
0-0.03 mg/kg b.w.
FURTHER WORK OR INFORMATION DESIRED
Observations in man.
Ashley, W.E. Acute oral test. Haskell Laboratory Report No. 585-74
1974 (Unpublished report submitted to WHO by E.I. DuPont de
Nemours & Co.).
Summers, J.C. Mutagenic activity of 1-cyano-N,N-dimethylformamide in
1978 the Salmonella/microsome assay. Haskell Laboratory Report
No. 284-78 (Unpublished report submitted to WHO by E.I.
DuPont de Nemours & Co.).
Willigan, D.A. Ninety-day feeding study in rats with 1-cyano-N,N-
1977 dimethyl-formamide (INN-79) metabolite of Vydate(R). Haskell
Laboratory Report No. 630-76 (Unpublished report submitted
to WHO by E.I. DuPont de Nemours & Co.).