ETHION
EXPLANATION
First draft prepared by Dr J.A. Quest,
US Environmental Protection Agency, Washington, D.C., USA
Ethion toxicity has been reviewed by several Joint Meetings
between 1968 and 1989 (Annex 1, FAO/WHO, 1969ab, 1973ab, 1983ab,
1986ad, 1987a, and 1989b). Data include pharmacokinetic studies in
rats, goats, and hens, in vitro and in vivo genotoxicity studies,
acute and short-term tests in rodents and dogs, carcinogenicity
studies in mice and rats, reproduction/teratogenicity studies in rats,
neurotoxicity examinations in hens, and a three-week oral study in
humans. The ADI was converted to a temporary ADI of 0-0.001 mg/kg bw
at the 1982 Joint Meeting. Further studies were reviewed at the 1986
Meeting, when the temporary ADI was raised to 0-0.006 mg/kg bw. The
temporary ADI was subsequently extended by the 1989 JMPR pending the
receipt of a required short-term (90 day) toxicity study in dogs and
a delayed neurotoxicity study in hens. These studies were reviewed by
the present Meeting.
EVALUATION FOR ACCEPTABLE INTAKE
BIOLOGICAL DATA
Toxicological studies
Short-term studies
Dogs
Purebred beagle dogs (4/sex/dose) were administered ethion (93.4%
pure) in the diet at dose levels of 0, 0.5, 2.5, 25, and 300 ppm for
90 days. These concentration levels were equivalent to doses of
approximately 0, 0.01, 0.06, 0.71 and 6.9 mg/kg bw/day in males and 0,
0.012, 0.07, 0.71 and 8.25 mg/kg bw/day in females. All dogs were
examined twice daily for mortality and moribundity, and once daily for
clinical signs of toxicity. Body weights and food consumption were
determined weekly. Ophthalmological examinations were performed
pretest and at week 13. Standard haematological and clinical
chemistry examinations were performed pretest and during weeks 5, 9,
and 13. Urinalysis was not performed. The weights of several organs
were determined and histopathological examination was performed on
gross lesions plus 31 organs/tissues.
Treatment-related toxicological effects were produced by the
three highest dose levels of ethion. Dose levels ranging from 2.5 to
300 ppm were associated with inhibition of plasma cholinesterase
activity at weeks 5, 9, and 13. Dose levels ranging from 25 to 300
ppm produced reductions in brain cholinesterase activity at the same
time intervals. The highest dose level of 300 ppm was also associated
with a variety of additional toxic effects in male and/or female dogs.
These included the sacrifice of one female on day 90 due to
malnutrition, emaciation and dehydration, clinical signs of toxicity
(emesis, salivation, miosis, tremors, thin body mass), reductions in
food consumption and body weight gain, 95% reduction in erythrocyte
acetylcholinesterase activity, decreases in serum albumin, calcium and
total protein levels, and increases in serum chloride and alanine
aminotransferase levels, and increases in relative liver weight (males
only), and gross pathological changes. In the female sacrificed in
extremis, these consisted of dark areas on the lung and adrenal, pale
and small spleen, thickened wall of the gallbladder, dark mucosa of
the jejunum, darkened and cystic mesenteric lymph nodes, one ovarian
cyst, and a small thymus. In dogs which were sacrificed at term,
changes included a pituitary cyst (one high dose male), a thickened AV
valve (one high dose male), small spleen (one high dose male), pale
area in the liver (one high dose male), and dark areas in the jejunum
(one male at 2.5 ppm, and one male and one female at 300 ppm). The
fact that the majority of these gross pathology findings were
exhibited in the high-dose groups suggested they may be treatment-
related. Ethion did not produce any adverse ophthalmological,
haemtological, or histopathological changes in any of the animals on
study. The NOAEL was 2.5 ppm (equal to 0.06 mg/kg bw/day).
Special studies on delayed neurotoxicity
The acute delayed neurotoxicity of ethion was assessed in adult
domestic hens. The study contained two parts. First, an LD50
determination was performed using oral (gavage) doses of 0, 889, 1333,
2000, 3000, and 4500 mg ethion/kg bw (10 hens/dose group). The
observed LD50 was 2792 mg/kg bw (14-day observation period). Most
deaths occurred within 1 to 48 hours after dosing. Toxic signs
included unsteadiness, wing-dropping, inability to stand, trembling,
and reductions in body weight. The 889 mg/kg bw dose of ethion was a
no-effect dose level. Second, a neurotoxicity assessment was
performed using groups of 10 hens. A vehicle control group was dosed
orally with corn oil, a positive control group with 500 mg/kg TOCP,
and four test groups were each dosed with the LD50 (2792 mg/kg bw).
The birds dosed with ethion were protected with 10 mg/kg i.m. atropine
sulfate. Dosing was followed by a 21-day observation period, a
redosing, and a final 21-day observation period. Surviving hens were
sacrificed at 42 days. Histopathological examination of brain, spinal
cord and peripheral nerve tissues were performed on 25 of the 40
animals dosed with ethion (these were the survivors to 42 days), 10/10
control hens, and 10/10 TOCP-treated hens.
The results indicated that ethion produced clinical signs of
toxicity (unsteadiness, leg stiffness, stumbling, inability to stand),
and reduction in food consumption and body weight during the 3-day
period following dosing on both occasions. However, no unusual
clinical signs of neurotoxicity, gross pathological organ changes, or
neuropathological (i.e. histological) effects on the control or
peripheral nervous system were observed. In contrast, hens treated
with TOCP displayed ataxia as well as significant axonal degeneration
in the brain and spinal cord, and in peripheral nerve (Roberts,
et al., 1986).
COMMENTS
The results of the 90-day toxicity study in dogs indicated that
cholinesterase activity in plasma was inhibited by dietary levels of
ethion of 2.5 ppm or more, and that cholinesterase activity in brain
was inhibited at 25 ppm or more. The highest dose level of 300 ppm
was also associated with erythrocyte cholinesterase inhibition,
clinical signs of toxicity (salivation, miosis and tremors), reduced
food consumption and reduced body weight gain. The NOAEL was based
upon inhibition of brain cholinesterase activity (2.5 ppm, equal to
0.06 mg/kg bw/day in males and 0.07 mg/kg bw/day in females). The
reduction in plasma cholinesterase activity at 2.5 ppm ethion was not
considered to be an adverse effect. Ethion did not cause signs of
delayed neurotoxicity in hens when given at a dose level equivalent to
the LD50.
In establishing an ADI, the Committee considered three studies on
ethion that have been reviewed. These were a rat teratogenicity study
previously evaluated at the 1986 JMPR, a human toxicity study
previously examined at the 1972 JMPR and the above-described 90-day
dietary toxicity study in dogs. The rat teratogenicity study
indicated a NOAEL of 0.2 mg/kg bw/day. The next highest dose level,
0.6 mg/kg bw/day, resulted in embryotoxicity/fetotoxicity, as
indicated by decreased fetal body weight and treatment-related delayed
ossification. The human study indicated a NOAEL of 0.15 mg/kg bw/day;
the only effect at this dose level was a reduction in cholinesterase
activity in plasma.
A comparison of the NOELs established on the basis of plasma
cholinesterase inhibition by ethion in humans (0.15 mg/kg bw/day) and
dogs (0.01 mg/kg bw/day) indicated that this response occurs at an
excessively low dose in the dog, and that for this reason the dog is
an inappropriate species for comparison. Therefore, the ADI was based
on the rat teratogenicity study to which a safety factor of 100 was
applied yielding an ADI of 0-0.002 mg/kg bw.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Rat: 0.2 mg/kg bw (embryotoxicity/fetotoxicity).
Dog: 2.5 ppm in the diet, equal to 0.06 mg/kg bw/day in
males and 0.07 mg/kg bw/day in females.
Human: 0.15 mg/kg bw.
Estimate of acceptable daily intake for humans
0-0.002 mg/kg bw
Studies which will provide information valuable in the
continued evaluation of the compound
Further observations in humans.
REFERENCES
Bailey, D.E. (1988). 90-Day Subchronic Toxicity Study of Ethion
Technical in Dogs. Unpublished report No. 104-229 from Hazleton
Laboratories America, Inc., Vienna, VA, USA. Submitted to WHO by FMC
Corporation, Princeton, NJ, USA.
Roberts, N.L., Phillips, C.N.K., Gopinath, C., and Fish, L.E. (1986).
Acute Delayed Neurotoxicity Study with FMC 1240 in the Domestic Hen.
Unpublished report No. FCC 81/851263 from Huntingdon Research Centre,
Ltd., Huntingdon, Cambridgeshire, UK. Submitted to WHO by FMC
Corporation, Princeton, NJ, USA.