PESTICIDE RESIDUES IN FOOD - 1997
Sponsored jointly by FAO and WHO
with the support of the International Programme
on Chemical Safety (IPCS)
TOXICOLOGICAL AND ENVIRONMENTAL
EVALUATIONS 1994
Joint meeting of the
FAO Panel of Experts on Pesticide Residues
in Food and the Environment
and the
WHO Core Assessment Group
Lyon 22 September - 1 October 1997
The summaries and evaluations contained in this book are, in most
cases, based on unpublished proprietary data submitted for the purpose
of the JMPR assessment. A registration authority should not grant a
registration on the basis of an evaluation unless it has first
received authorization for such use from the owner who submitted the
data for JMPR review or has received the data on which the summaries
are based, either from the owner of the data or from a second party
that has obtained permission from the owner of the data for this
purpose.
FENTHION (addendum)
First draft prepared by
A. Moretto
Istituto di Medicina del Lavoro
Università degli Studi di Padova, Padua, Italy
Explanation
Evaluation for acute reference dose
Acute toxicity
Comments
Toxicological evaluation relevant for establishing an acute
reference dose
Reference
Explanation
Fenthion was reviewed most recently by the 1995 JMPR (Annex 1,
reference 74), which established an ADI of 0-0.007 mg/kg bw on the
basis of an NOAEL of 0.07 mg/kg bw per day (the highest dose tested)
for inhibition of erythrocyte acetylcholinesterase activity in a
25-day study in volunteers. The available data did not permit the
Meeting to establish an acute reference dose different from the ADI. A
study of neurotoxicity in rats given a single dose was available to
the present Meeting to assist in reviewing the acute reference dose.
Evaluation for acute reference dose
Acute toxicity
Rats
Technical-grade fenthion (purity, 94.6%) dissolved in corn oil was
administered by gavage at a volume of 5 ml/kg bw to groups of 18 male
and 18 female fasted adult Wistar rats at doses of 0 (vehicle), 1, 50,
or 125 mg/kg bw for males and 0, 1, 75, or 225 mg/kg bw for females.
Twelve animals in each group were observed for clinical signs, death,
and body weight and underwent a functional observational battery of
tests and automated measurements of activity (figure-eight maze);
after death, the brains were weighed and a gross necropsy was
performed. Skeletal muscle, peripheral nerves, eyes with optic nerves,
and tissues from the central nervous system were examined
microscopically. After a preliminary experiment, behavioural testing
was started on the day of treatment (day 0), at the beginning of the
peak effect, a minimum of 5 h after application. The activities of
plasma, erythrocyte, and brain cholinesterases were determined about
5.5 hours after treatment (i.e. at the peak of clinical
manifestations) in the remaining six animals in each group.
Four females at the high dose died within three days of treatment, and
dose-related cholinergic signs were seen in animals at the
intermediate and high doses. The clinical signs persisted up to five
days after treatment. Body weight was decreased in males at the high
dose on day 7, and recovery was not complete by day 14. Females at the
high dose had marginally decreased body weights at day 7 only. The
functional observational battery of tests revealed dose-related
effects on the day of treatment in males and females at the two higher
doses. These effects were associated with signs of acute cholinergic
toxicity, most of which were reversed by day 14. Decreased motor and
locomotor activity in the figure-eight maze were also seen in animals
at these doses on day 0, with almost complete recovery by day 14. At
the time of functional and motor activity testing on day 0, plasma and
erythrocyte cholinesterase activities were inhibited in males and
females at the intermediate dose (by 89-95%) and high dose (by
90-96%); females at the low dose showed marginal inhibition of plasma
(by 23%) and erythrocyte cholinesterase activity (by 22%). Brain
acetylcholinesterase activity was inhibited by 76% in animals at the
intermediate dose and by 86% in those at the high dose; in rats at the
low dose, it was inhibited by 4% in males and 9% in females, the
latter being statistically significant. The only treatment-related
gross lesion was emaciation in the four females at the high dose that
died before terminal sacrifice. Terminal brain weight was not
affected. There were no treatment-related microscopic lesions in
skeletal muscle or neural tissues. The NOAEL for both inhibition of
brain acetylcholinesterase activity and neurobehavioural effects was
1 mg/kg bw (Dreist & Popp, 1997).
Comments
In rats treated by gavage with single doses of 0, 1, 50 (males), 75
(females), 150 (males), or 225 (females) mg/kg bw of technical-grade
fenthion, the NOAEL for inhibition of brain acetylcholinesterase
activity and for neurobehavioural effects was 1 mg/kg bw.
In a study that was reviewed by the 1995 JMPR, administration of 0.07
mg/kg bw to volunteers daily for about 25 days did not inhibit
erythrocyte acetylcholinesterase activity.
The Meeting concluded that an acute reference dose of 0.01 mg/kg bw
could be allocated by taking into account the NOAEL of 1 mg/kg bw in
rats and applying a safety factor of 100.
Toxicological evaluation relevant for establishing an acute
reference dose
Levels that cause no toxic effect
Rat: 1 mg/kg bw (single oral administration, inhibition of
brain acetylcholinesterase activity)
Human: 0.07 mg/kg bw per day (four-week study in volunteers,
highest dose tested)
Estimated acute reference dose for humans
0.01 mg/kg bw
Reference
Dreist, M. & Popp, A. (1997) E 1752 (common name: fenthion). Acute
oral neurotoxicity screening in Wistar rats. Unpublished report No.
26113 from Bayer AG, Toxicology, Wuppertal, Germany. Submitted to WHO
by Bayer AG, Leverkusen, Germany.
See Also:
Toxicological Abbreviations
Fenthion (ICSC)
Fenthion (WHO Pesticide Residues Series 1)
Fenthion (WHO Pesticide Residues Series 5)
Fenthion (Pesticide residues in food: 1977 evaluations)
Fenthion (Pesticide residues in food: 1978 evaluations)
Fenthion (Pesticide residues in food: 1979 evaluations)
Fenthion (Pesticide residues in food: 1980 evaluations)
Fenthion (Pesticide residues in food: 1983 evaluations)
Fenthion (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)
Fenthion (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)