VAMIDOTHION
EXPLANATION
Vamidothion was evaluated by the Joint Meetings in 1973, 1982 and
1985 (Annex I, FAO/WHO 1974b, 1985b, 1986b). A temporary ADI was
allocated in 1981. A toxicological monograph was prepared by the Joint
Meeting in 1973 and monograph addenda were prepared in 1982 and 1985.
Additional studies required by 1988 to complete the toxicological
data base were a multi-generation reproduction study and a one-year
dog study. These data have now been received and are reviewed in this
monograph addendum.
EVALUATION FOR ACCEPTABLE INTAKE
Toxicological studies
Special studies on reproduction
Rats
In a 2-litter, 2-generation reproduction study, groups of male
and female Sprague-Dawley CD rats (30/sex/group in the F0 generation
and 24/sex/group in the F1 generation) were administered by oral
gavage 0, 0.05, 0.5 or 5.0 mg vamidothion (purity:technical)/kg bw as
an aqueous solution. The F0 generation, as well as the F1
generation, received 14 weeks' treatment before pairing to produce
F1 and F2 litters, respectively (dosing of the F1 animals
commenced at weaning and continued until termination after the
breeding phase). All adult animals were subjected to a detailed
necropsy procedure and the reproductive organs were weighed and
retained; histological examination was performed on tissues from the
control and high-dose group animals. Parental animals were observed
for clinical signs, mortality, body weight and food consumption.
Offspring was observed for number of live and dead foetuses, pup
weight and sex, clinical signs, mortality and litter size. Those F1
weanlings not selected for continuation of the study and F2
weanlings were examined for macroscopic abnormalities. Plasma,
erythrocyte and brain cholinesterase determinations were conducted at
final sacrifice of F0 and F1 adults (10/sex) at the termination of
each generation and of F1 and F2 offspring (5/sex) one week after
weaning and at weaning, respectively.
No effects were observed on reproduction parameters. The only
effect observed was inhibition of cholinesterase. Parental
cholinesterase activity was reduced at 5.0 and 0.5 mg/kg bw.
Erythrocyte cholinesterase inhibition was about 90% and 50%,
respectively, and plasma cholinesterase about 70% and 40%,
respectively. In F0 and F1 parents, brain cholinesterase activity
was decreased about 30% (20-39%) at 5.0 mg/kg bw. At 0.5 mg/kg bw only
a slight but statistically significant inhibition of 5-8.5% was
observed in F0 and F1 parents. This is not considered as
toxicologically relevant. At 0.05 mg/kg bw erythrocyte cholinesterase
was slightly inhibited (about 5-20%) in F0 parents only. In F1
parents, only plasma cholinesterase was slightly inhibited (about
15%). Only high-dose weanlings of the F1 generation had depression
of erythrocyte and plasma cholinesterase activity, but it was to a
lesser extent than parents. Based on the effects on cholinesterase in
brain, the NOAEL is 0.5 mg/kg bw. (Willoughby et al., 1988).
Short-term toxicity
Dogs
Groups of 21-23 week old beagle dogs (6/sex/group) were orally
administered 0, 0.05, 0.5 or 5.0 mg vamidothion/kg/day for 52 weeks. A
vamidothion/methylethylketone mixture (500 g/l) was dissolved in
polypropylene glycol and incorporated into gelatin capsules (freshly
prepared weekly) for administration. Observations included clinical
signs, mortality, food and water consumption, body weight,
ophthalmoscopy, haematology, clinical chemistry, urinalysis, plasma,
erythrocyte and brain cholinesterase, macroscopy, organ weight and
histopathology. Samples of liver, kidney cortex and kidney medulla
from control and high-dosed animals were examined by transmission
electron microscopy.
No effects were seen on most parameters. Diarrhoea was observed
in high-dosed males and stiff gait of the hind legs was occasionally
observed in 5/6 male and 5/6 female dogs during the first 10 weeks of
the experiment. SAP, ALAT and to a lesser extent ASAT activity were
increased in males at 5.0 mg vamidothion/kg bw. Plasma and erythrocyte
cholinesterase activity were significantly inhibited at 5.0 and
0.5 mg/kg bw (plasma: about 50 and 30%, respectively; erythrocytes:
about 90 and 40%, respectively). Plasma cholinesterase was also
decreased in males (5-10%) at 0.05 mg/kg but this is not considered
toxicologically relevant. Brain cholinesterase activity was
significantly reduced at the highest dose only (20-30%). The NOAEL in
this study was 0.5 mg vamidothion/kg bw based on the effect on brain
cholinesterase (West et al, 1988a; 1988b).
Observations in man
Groups of 6-11 normal healthy volunteers of both sexes were
administered 9.6 or 37.2 µg vamidothion/kg/day orally in aqueous
solution on five days each week for three weeks. Other groups received
78.8 or 122.8 µg vamidothion/kg/day in aqueous solution for five
weeks. A control group was studied for 25 weeks. No clinical signs or
symptoms were found which could be attributed to treatment. Plasma
cholinesterase, estimated weekly, showed no consistent depression in
any group but erythrocyte cholinesterase was depressed in three of six
volunteers receiving 122.8 µg/kg/day. The no-effect level was
considered to be 78.8 µg/kg/day (calculated to be equivalent to
56.3 µg/kg/day if vamidothion was administered every day without a
break) (Noel et al., 1970). (From 1973 JMPR Evaluations.)
COMMENTS
In a 2-generation reproduction study in rats, vamidothion had no
effect on reproductive performance, survival, growth or development.
In this study treatment-related decreases in plasma cholinesterase and
erythrocyte acetylcholinesterase activities were observed in parental
rats at 5.0 and 0.5 µg/kg bw. F1 weanlings showed these effects at
5.0 mg/kg bw. Inhibition of brain acetylcholinesterase was observed at
5.0 mg/kg bw in the parent animals.
In a one-year toxicity study in dogs, inhibition of brain
acetylcholinestarase was found at 5.0 mg/kg bw/day. Plasma
cholinesterase and erythrocyte acetylcholinesterase were inhibited at
5.0 and 0.5 mg/kg bw.
The 1973 JMPR reviewed a study in human volunteers. In this study
inhibition of erythrocyte acetylcholinesterase was observed at a dose
level of 0.123 mg/kg bw/day, given 5 days per week for 5 weeks. An ADI
based on the human data was estimated.
TOXICOLOGICAL EVALUATION
CAUSING NO TOXICOLOGICAL EFFECT
Mouse: 1 ppm in the diet, equal to 0.137 mg/kg bw
Rat: 1 ppm in the diet, equal to 0.054 mg/kg bw
Dog: 0.5 mg/kg bw
Man: 0.08 mg/kg bw/day
ESTIMATE FOR ACCEPTABLE DAILY INTAKE FOR MAN
0-0.008 mg/kg bw
STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED
EVALUATION OF THE COMPOUND
Further observations in man.
REFERENCES
Noel, P.R.B., Hayes, G. & Street, A.E. 1970. Vamidothion:
Determination of no-effect level in human volunteers. Unpublished
report of Huntingdon Research Centre, submitted by Rhône-Poulenc to
the JMPR in 1973.
West, H., Virgo, D.M., Wooley, A.P.A.H., Lee, P., Fowler, J.S.L. &
Brown, P.M. 1988a. Vamidothion: toxicity study by oral (capsule)
administration to beagle dogs for 52 weeks. Unpublished report
No. 87/RHA074/94 d.d. 8 March 1988 from Life Science Research, Eye,
Suffolk IP23 7PX, England. Submitted to WHO by Rhône-Poulenc
Agrochemie, Boite Postale 9163, F-69263 Lyon Cedex 09, France.
West, H., Wallace, W., Sykes, A.K. & Fowler, J.S.L. 1988b.
Vamidothion: toxicity study by oral (capsule) administration to beagle
dogs for 52 weeks. First supplement to LSR report No. 87/RHA074/904,
electron microscopy report. Unpublished report No. 88/RHA074/137 d.d.
30 March 1988 from Life Science Research, Eye, Suffolk IP23 7PX,
England. Submitted to WHO by Rhône-Poulenc Agrochemie, Boite Postale
9163, F-69263 Lyon Cedex 09, France.
Willoughby, C.R., Tesh, J.M., Enticott, J. & Fowler, J.S.L. 1988.
Vamidothion: effects upon reproductive performance of rats treated
continuously throughout two successive generations. Vol. I, II and
III. Unpublished report No. 88/RHA098/144 d.d. 4 May 1988 from Life
Science Research, Eye, Suffolk IP23 7PX, England. Submitted to WHO by
Rhône-Poulenc Agrochemie, Boite Postale 9163, F-69263 Lyon Cedex 09,
France.