TRIAZOPHOS
First draft prepared by Mr M. Watson,
Ministry of Agriculture, Fisheries and Food,
Harpenden, Hertfordshire, United Kingdom
EXPLANATION
Triazophos was evaluated for acceptable daily intake by the 1982
JMPR (Annex I, 38) at which time a temporary ADI of 0-0.0002 mg/kg bw
was established. A toxicological monograph was published after that
meeting (Annex I, 39). Additional studies required to complete the
toxicological data base were a carcinogenicity study, a teratology
study in at least one mammalian species, metabolism studies in
additional mammalian species (to explain species differences in acute
toxicity studies) and mutagenicity studies. Further studies of
biochemical aspects, a range of mutagenicity studies and teratology
studies in rats and rabbits were submitted for evaluation at the 1986
Joint Meeting (Annex I, 47). After consideration of these results the
temporary ADI of 0-0.0002 mg/kg bw was extended but the final
determination of an ADI was considered impractical since no
carcinogenicity study was available.
The results of carcinogenicity studies in rats and mice and
additional studies that were submitted to the present meeting are
summarized in this monograph addendum.
EVALUATION FOR ACCEPTABLE INTAKE
BIOLOGICAL DATA
Biochemical aspects
Effects on enzymes and other biochemical parameters
Groups of 10 male and 10 female Wistar-derived rats were fed
dietary levels of triazophos at 0, 3, 10 or 200 ppm for 48 weeks. The
treatment period was followed by a withdrawal period of 7 weeks during
which all rats received untreated diets. Cholinesterase activity in
plasma and red blood cells was determined in all rats at weeks 33 and
43 and during the withdrawal period at 3, 7, 14, 28 and 49 days. At
the end of the withdrawal period all rats were killed and
cholinesterase activity in the brain was determined in 5 males and 5
females from each group. Cholinesterase activities in plasma and
erythrocytes were distinctly inhibited at 10 ppm and considerably
inhibited at 200 ppm. Three days after discontinuing treatment with
triazophos, the plasma cholinesterase activity in males had returned
to normal. In females (which were more severely affected during the
treatment period), this recovery was observed within 7 days. Recovery
of cholinesterase activity in red blood cells took much longer.
Values were generally similar to controls after 2 to 4 weeks recovery
at 10 ppm and after 4 to 7 weeks recovery at 200 ppm. There were no
inter-group differences in brain cholines-terase activity at
termination (Til & Leegwater, 1974).
The acute oral toxicity of triazophos (dissolved in arachis oil)
was determined in groups of female rats, and the effects of different
antidote therapies were investigated. Antidotes were injected
intraperitoneally, 1.5 minutes after dosing with triazophos.
Different antidotes (atropine sulphate, atropine methylnitrate,
pralidoxime mesylate and obidoxime) were tested alone and in
combination, but no attempt was made to investigate optimally
effective doses of antidote. From the results of this study it may be
concluded that atropines raise the LD50 of triazophos by a factor of
about 1.5. The addition of pralidoxime to atropines does not increase
the LD50 any further, but a combination of atropines and obidoxime
raises the LD50 by a factor of about 2. There was some indication
that the toxic effects of triazophos are longer lasting than the
antidote effects of atropines and oximes and that repeated dosing with
antidotes may be beneficial, although this hypothesis was not tested
directly in the experiment. The study design of this experiment was
inadequate to investigate the true effects of oxime antidotes on
anti-cholinesterase poisoning induced by triazophos (Cohen, 1971).
Toxicological studies
Short-term studies
Rats
In a 4-week study, triazophos (purity 97.6%) was administered via
inhalation exposure (nose only) to 4 groups of 10 male and 10 female
Wistar rats at concentrations of 0 (Control), 1, 5 and 25 mg/m3 for
6 hours per day, 5 days per week. An additional 5 males and 5 females
per group were used for a 4-week recovery period after completion of
treatment. There were no treatment-related clinical signs and the
only death was associated with collection of a blood sample. Body
weight gain and food intake remained undisturbed by treatment and
haematological and biochemical data apart from cholinesterase
investigations revealed no changes of toxicological significance.
Depression of cholinesterase activity in plasma and erythrocytes was
more marked in females than in males; males were affected only at the
high dose, whereas females were affected at 5 and 25 mg/m3. A
treatment-related depression of brain cholinesterase activity was,
however, seen only in males at the high dose. Pathological
investigations, including histopathology, revealed no indication of
any reaction to treatment. The depression of cholinesterase activity
was completely reversible at the end of the 4-week recovery period.
The NOAEL was 5 mg/m3, based on the depression of
acetylcholinesterase activity in brain at 25 mg/m3 (Bernstein
et al., 1987).
In a 4-week study, triazophos (purity 97.6%) was administered via
dermal exposure (under an occlusive dressing) to 4 groups of 10 male
and 10 female Wistar rats at dose levels of 0 (Control), 0.5, 5 and 50
mg/kg bw for 6 hours per day, 5 days per week. An additional 5 males
and 5 females per group were used for a 4-week recovery period after
completion of treatment. There were no clinical signs of reaction to
treatment, no treatment-related deaths and food intake and weight
change remained unaffected. Haematological investigations revealed no
indication of any reaction to treatment. A slightly increased glucose
and urea level was noted for males receiving 5 mg/kg and both sexes
receiving 50 mg/kg as well as decreased triglycerides and increased
serum alanine aminotransferase activity for males receiving the high
dose. Cholinesterase activity was inhibited in plasma in females
receiving 0.5 mg/kg bw/day and in both sexes at 5 and 50 mg/kg bw/day.
Erythrocyte cholinesterase was inhibited at 5 and 50 mg/kg bw/day in
both sexes and brain acetylcholinesterase activity was inhibited only
at the high dose level. At pathological investigations, including
histopathology, the only sign of reaction to treatment was a slight
increase in adrenal weight in females treated with 5 or 50 mg/kg
bw/day. All of the changes seen during the treatment period were
reversible during the withdrawal period. The no observable adverse
effect level was 0.5 mg/kg bw/day, based on the clinical chemistry and
organ weight changes seen at 5 and 50 mg/kg bw/day (Thevenez et al.,
1987).
In a 13-week dietary toxicity study, triazophos (purity 92.6%)
was administered to groups of 10 male and 10 female Wistar rats at
dietary concentrations of 0 (Control), 1, 20 and 400 ppm. In order to
investigate recovery from any reaction to treatment in a 4-week
withdrawal period, an additional 10 animals per sex were added to the
control, mid and high dietary level groups. There were no clinical
signs of reaction to treatment and no rats died prior to the scheduled
necropsy. A slight increase in food intake was noted for females
receiving 400 ppm, although body weight gain remained unaffected by
treatment. Hematological investigations revealed evidence of a very
slight degree of anaemia in rats treated with 400 ppm. Investigation
of cholinesterase activity revealed a dose-related depression in
plasma and erythrocyte activity at 20 and 400 ppm and a depression in
activity in brain at 400 ppm. Pathological investigations at
termination revealed no evidence of any reaction to treatment with
triazophos. All the changes seen during the treatment period were
reversible during the withdrawal period. The
no-observable-adverse-effect-level was 20 ppm, equal to 1.5 mg/kg
bw/day, based on the inhibition of brain cholinesterase activity at
400 ppm (Tennekes et al., 1986).
Dogs
In a 13-week study, groups of beagle dogs received triazophos
(purity 92.6%) by dietary administration at levels of 0 (control),
0.3, 9.0 and 270/180 ppm. The control, mid- and high-dose groups
consisted of 6 males and 6 females, while the low-dose group was
composed of 4 dogs of each sex. After completion of the treatment
period, recovery from treatment-related effects was investigated in 2
males and 2 females from the control and mid-dose group. Severe
cholinergic clinical signs of reaction to treatment were seen at the
high dose. Two males and one female from this group were killed in a
moribund condition on days 43, 81 and 55, respectively. The dietary
level for the high-dose group was reduced from 270 to 180 ppm from day
33 onwards. Body weight loss and decreased food intake were seen at
the high dose, but not at lower doses. Haematological and biochemical
changes were seen in dogs receiving 270/180 ppm but these were
probably secondary to the poor general health of these animals.
Inhibition of cholinesterase activity in plasma was seen at all dose
levels, erythrocyte acetylcholinesterase was inhibited in dogs
receiving 9.0 or 270/180 ppm and brain acetylcholinesterase was
inhibited only in dogs receiving the high dose. Pathological
investigations revealed treatment-related changes only at the high
dose. These consisted of muscular hypertrophy in the duodenal wall,
degenerative/inflammatory lesions in the zygomatic gland and
mineralization of the fibrous-muscular tissue of the left ventricular
papillary muscle. Changes in cholinesterase activity in mid-dose dogs
were reversible during the recovery period. The NOAEL was 9.0 ppm,
equal to 0.29 mg/kg bw/day, based on the severe effects, including
mortality, seen at the high dose (Bloch et al., 1986).
In a 52-week study, groups of beagle dogs received triazophos by
dietary administration at levels of 0, 0.2, 0.4, 4 or 80 ppm. The
control and high-dose groups consisted of 6 males and 6 females while
the other groups were composed of 4 dogs of each sex. Treatment with
triazophos at 80 ppm was associated with the sacrifice of one female
on day 73 and the termination of treatment in a second female from day
106. Both of these dogs showed signs typical of cholinesterase
inhibition (persistent diarrhoea, evidence of dehydration, weight
loss). The withdrawal of treatment in the second female was followed
by a progressive recovery, although cholinesterase activity remained
below control and pre-test values. Apart from the two females from
the high-dose group mentioned above, diarrhoea was seen in most
high-dose dogs and a few dogs receiving 4 ppm while evidence of
dehydration and weight loss was seen in an additional male receiving
4 ppm. Investigations of auditory perception, ophthalmoscopy,
haematological investigations and clinical chemistry tests including
urinalysis but apart from cholinesterase investigations revealed no
changes considered to be of any toxicological significance. The
assessment of plasma and erythrocyte cholinesterase activity indicated
a dose-dependent inhibition for both sexes receiving 4 or 80 ppm.
Minor variations in cholinesterase activity at lower doses were
considered not to be of toxicological significance and brain
cholinesterase activity remained unaffected by treatment in all
groups. Pathological investigations at termination of the study,
including autopsy findings, organ weight analysis and
histopathological examination of tissues revealed no evidence of any
reaction to treatment with triazophos. The NOAEL was 4 ppm (equal to
0.12 mg/kg bw/day) based on inhibition of cholinesterase activity and
signs of reaction to treatment, including mortality, at 80 ppm (Allen
et al., 1989).
Monkeys
Groups of one male and one female adult rhesus monkeys were given
daily oral doses of triazophos (suspended in starch slurry) of 0.025
or 0.05 mg/kg bw by stomach intubation for 22 consecutive days.
Behaviour, general condition, body weight and food intake of the
animals was monitored. Blood samples were collected for determination
of serum and erythrocyte cholinesterase activity pre-test, after each
dose and twice weekly after the last dose for 6 weeks. Behaviour and
general condition of the animals was not affected by treatment and
food consumption was affected only in the male monkey receiving the
high dose. This animal ate 40-45% less than expected during the
treatment period, but intake returned quickly to normal after
cessation of dosing. Body weight remained unaffected by treatment in
all animals. Serum cholinesterase activity in animals receiving
0.05 mg/kg bw/day fell rapidly to about 30-35% of the initial value,
with the maximum decrease being seen after 5-8 days dosing. After the
last dose, activities increased continuously, approaching the initial
value after 18-22 days withdrawal. At the lower dose, serum
cholinesterase activity fell to about 40% of initial activity in the
female and 70% in the male. Lowest values were seen after about 18
days dosing and values increased after the end of the dosing period;
reaching initial values after 8 days withdrawal in the male and 15
days in the female. Erythrocyte cholinesterase activity remained
unaffected by treatment at either 0.025 or 0.05 mg/kg bw/day (Scholz
& Baeder, 1971).
Long-term/carcinogenicity studies
Mice
In a combined long-term toxicity and carcinogenicity study in
mice, triazophos was administered via the diet to four groups of 60
male and 60 female NMRI mice at dietary levels of 0, 6, 30 or 150 ppm.
From each group 10 males and 10 females were designated for interim
sacrifice after 52 weeks and the remaining 50 males and 50 females
comprised the carcinogenicity study and were scheduled for sacrifice
after 104 weeks.
There were no clinical signs of reaction to treatment and
although mortality at the high dose was slightly higher than in
controls, this difference did not attain statistical significance.
Survival at the terminal sacrifice was in the range of 46 - 52% in the
control, 6 and 30 ppm groups and 38% in the high dietary level group.
Food intake and weight gain remained largely unaffected by treatment
and hematological parameters also remained unaffected by treatment
with triazophos. Clinical chemistry investigations revealed
treatment-related changes in cholesterol levels and cholinesterase
activity. At the 12-month interim sacrifice serum cholesterol levels
were increased, compared to controls in high dose male mice; a
similar, though not statistically significant, change was seen at the
terminal sacrifice in males treated with 30 or 150 ppm. At the
interim sacrifice, serum cholinesterase activity was inhibited at 30
and 150 ppm, and erythrocyte cholines-terase was inhibited in males at
150 ppm and in females at 30 and 150 ppm. More severe effects were
seen at the terminal sacrifice: serum and erythrocyte cholinesterase
were inhibited, compared to controls, in all groups, apart from
erythrocyte activity in males treated with the low dose. Brain
cholinesterase activity was not affected by treatment after 52 weeks
but at the terminal sacrifice a marked inhibition was seen in females
treated with 150 ppm, though not in any other group. Pathological
investigations at the interim and terminal sacrifices revealed no
indication of any reaction to treatment with triazophos. In
particular, the type and incidence of neoplastic lesions were those
commonly seen in aged mice. The NOAEL was thus 30 ppm, equal to
4.5 mg/kg bw/day, based on the slightly increased mortality seen in
animals treated with 150 ppm and inhibition of brain cholinesterase in
females at 150 ppm (Donaubauer et al., 1989).
Rats
In a combined long-term toxicity and carcinogenicity study in
rats, triazophos was administered via the diet to four groups of 80
male and 80 female Wistar-derived rats at dietary levels of 0, 3, 27,
or 243 ppm. From each group, 10 males and 10 females were designated
for interim sacrifice after 52 weeks, 20 males and 20 females for
sacrifice after 104 weeks, while the remaining 50 males and 50 females
in each group comprised the carcinogenicity study and were scheduled
for sacrifice after 118 weeks of treatment. There were no clinical
signs of reaction to treatment and mortality remained unaffected by
administration of triazophos. Survival at the terminal sacrifice was
in the range of 46-51% in the different groups. Female rats in the
high dose group ate about 10% more food than control rats and this was
reflected in an increased body weight gain in this group; otherwise
appetite and growth remained unaffected by treatment. In general,
treated females tended to drink more water than did the controls, this
effect was most evident at the high dietary level but males remained
unaffected. Hearing tests and ophthalmoscopy revealed no
treatment-related changes. Haematology and urinalysis investigations
revealed no indication of any reaction to treatment and
treatment-related changes in clinical biochemistry tests were confined
to the inhibition of cholinesterase activity. There was a
dose-related inhibition of cholinesterase activity in plasma and
erythrocytes at 243 and 27 ppm during the course of treatment. In
females treated with 243 ppm a slight (approximately 21-28%)
inhibition of brain cholinesterase activity was noted at both the
interim (52 week) and chronic toxicity (104 weeks) sacrifices.
Post-mortem examinations revealed no indication of any effect on organ
weights but there was a higher incidence of nodular changes in the
pancreas and small intestine in males treated with 243 ppm than in
controls. This correlated with an increased incidence of focal or
multifocal hyperplasia of the exocrine pancreas in treated groups.
This change was seen in 9 males at 243 ppm, 5 males at 27 ppm and 1
male at 3 ppm, but not in any controls. This lesion was not found in
any female rats from any group. The incidence and distribution of
tumours remained unaffected by treatment; all the neoplastic lesions
encountered were of types frequently seen in the strain of rat used in
this study. The NOAEL was thus 3 ppm, equal to 0.17 mg/kg bw/day
based on the increased incidence of hyperplasia of the exocrine
pancreas observed at 243 and 27 ppm in addition to inhibition of brain
cholinesterase in females at 243 ppm (Tennekes et al., 1990).
Reproduction studies
In a two-generation (one litter per generation) reproduction
study, groups of 25 male and 25 female Wistar rats received dietary
administration of triazophos at 0, 3, 27 or 243 ppm. Dietary levels
were based on the results of a preliminary study (Suter & Terrier,
1989). Treatment was continued for a 70 day premating period, and
throughout pairing, gestation and lactation for breeding of the F1
litters. Following weaning on day 21 post-partum, groups of 25 male
and 25 female F1 animals were selected. Diets were fed to these
animals for 125 days prior to pairing, and throughout pairing,
gestation and lactation for breeding of the F2 litters. Clinical
signs of reaction to treatment were seen at 243 ppm. Aggressive
behaviour was noted in the parental generation during the premating
period; exophthalmia, ataxia, tremors and dyspnoea were noted during
the lactation period in the females of the parental and F1
generations and in F1 pups for up to 3 weeks at the start of the
premating period. Three F1 generation females receiving 243 ppm died
during the lactation period. Treatment-related reductions in food
intake and weight gain were noted at 243 ppm, and a higher breeding
loss was also seen at the high dietary level than in the control
group. Reproductive index and general fertility parameters remained
unaffected by treatment at all dietary levels and there was no
evidence of any obvious teratogenic effect. Organ weights and
pathological examination gave no indication of any reaction to
treatment and behaviour, food intake and weight gain and pup viability
remained unaffected by treatment at 3 or 27 ppm. The NOAEL was thus
27 ppm, equivalent to 2-3 mg/kg bw/day (Suter et al., 1989).
Special studies on delayed neurotoxicity
An acute delayed neurotoxicity study was performed in hens.
Preliminary investigations of the acute oral toxicity revealed that
the LD50 in white Leghorn hens was 7.5 (4.8-10.1) mg/kg bw, and that
protection with atropine sulfate and 2-PAM methiodide raised the LD50
to approximately 50 mg/kg. In the main study, triazophos was
administered twice, orally, at the protected LD50 dose of 50 mg/kg bw
to a group of 20 white Leghorn hens, with an interval of 21 days
between doses. A negative control group and a positive control group
(TOCP 500 mg/kg bw), each composed of 6 animals, were also included in
the study. Dosing with triazophos resulted in the death of 15 animals
and the sacrifice of one further animal on day 38, despite symptomatic
treatment with antidotes. Deaths occurred within 24 hours of dosing,
9/20 after the first dose and a further 6 after the second. Of the
four hens which survived to the end of the study, two showed slight to
severe signs of ataxia. In one animal signs were seen 7 days after
the second dose and in the other 12 days after the second dose. These
clinical signs were accompanied by histological lesions in the spinal
cord (cystic dilatation in myelin sheaths and plaque-shaped
decomposition bodies). Similar histological lesions were also present
in the hen which showed no ataxia but was killed on day 38. Animals
in the positive control group showed the typical neurotoxic effects
produced by TOCP (Ebert & Mayer, 1988).
In a further acute delayed neurotoxicity test, triazophos was
administered twice at a dose level of 12.5 mg/kg bw to a group of 15
white Leghorn hens protected by an antidote treatment with an interval
of 21 days between doses. A negative control group and a positive
control group (TOCP 500 mg/kg bw), each composed of 6 animals, were
also included in the study. All hens treated with triazophos survived
and were killed at the end of the study. Cholinergic symptoms such as
lacrimation and trembling were seen shortly after dosing with
triazophos. Assessment of ataxia and histological examination of
brain, spinal cord and peripheral nerves indicated no neurotoxic
effects of triazophos. In contrast, animals in the positive control
group, treated with TOCP, showed the typical neurotoxic effects such
as severe delayed ataxia or paralysis and histological lesions such as
axonal swellings in the spinal cord and decomposition of the myelin
sheaths together with reactive proliferation of the Schwann's cells in
peripheral nerves (Ebert, 1989).
Neurotoxicity has also been investigated via short term, dietary
administration of triazophos. In a 20-day preliminary study,
triazophos was administered to groups of five female white Leghorn
hens by dietary admixture, at levels of 0 (control), 50, 100, 150 or
200 ppm. At termination, three animals from each group were assigned
for pathology (preservation of tissues only) and two for determination
of neuropathy target esterase (NTE) activity. All animals survived
until termination, there were no clinical signs of reaction to
treatment, and food intake, weight change, forced motor activity and
NTE activity remained undisturbed by treatment.
In the main study, triazophos was administered to groups of 10
female, white Leghorn hens by dietary admixture, at levels of 0
(control), 50, 110 or 250 ppm. There were no treatment-related
clinical signs among animals receiving 50 or 110 ppm. At 250 ppm,
restless and/or excited behaviour was seen in all animals and sedation
in 2/10. One of these latter two hens died on day 76. At 50 and 110
ppm food intake was initially reduced compared to controls but was
unaffected overall. At 250 ppm food intake was consistently reduced.
Treated animals displayed a dose-related weight loss during the study.
Examination of forced motor activity revealed no treatment-related
changes at 50 or 110 ppm, while at 250 ppm, two of the ten animals
displayed symptoms characteristic of delayed neurotoxicity. One of
these died on day 76. Plasma cholinesterase activity was markedly
reduced at all dose levels. NTE activity was not investigated.
Patho-logical examination revealed no treatment-related macroscopic
changes. Histo-logical examination revealed morphological evidence of
short-term neuro-toxicity in the spinal cord and peripheral nerves in
animals treated with 250 ppm. Similar lesions were seen in control
and treated hens, but the severity of the lesions and the number of
animals affected was greater at the high dietary level than in the
other groups (Ullmann et al., 1991).
Special studies on skin sensitization and irritation
The dermal sensitization potential of triazophos has been tested
in guinea pigs according to the Buehler patch test method. The
induction phase was carried out by repeated dermal application of a
10% solution of triazophos in sesame oil. At challenge (using a 5%
solution) no dermal reaction was seen and it was concluded that
triazophos displayed no sensitizing potential in this test (Hollander
& Weigand, 1976).
COMMENTS
In 1986 the temporary ADI of 0-0.0002 mg/kg bw was extended
pending the submission of a carcinogenicity study.
In a 52-week study in dogs, employing dietary concentrations of
0, 0.2, 0.4, 4, or 80 ppm triazophos, the only signs of reaction to
treatment were associated with inhibition of plasma and erythrocyte
cholinesterase activity. The NOAEL was 4 ppm (equal to 0.12 mg/kg
bw/day), based on inhibition of plasma and erythrocyte cholinesterase
activity and mortality at 80 ppm.
Long-term/carcinogenicity studies in rats and mice at dietary
concentrations of 0, 3, 27, or 243 ppm and 0, 6, 30 or 150 ppm
demonstrated that triazophos has no carcinogenic potential in either
species. In rats an increased incidence of hyperplasia of the
exocrine pancreas was observed at 27 and 243 ppm and inhibition of
brain acetylcholinesterase in females at 243 ppm. The NOAEL was 3
ppm, equal to 0.17 mg/kg bw/day. In mice, slightly increased
mortality at 150 ppm and inhibition of brain acetylcholinesterase in
females at 150 ppm were observed. The NOAEL was 30 ppm, equal to
4.5 mg/kg bw/day.
In a two-generation reproduction study in rats at dietary
concentrations of 3, 27 or 243 ppm triazophos, marked clinical signs,
including mortality, decreased survival and reduced weight gain in
pups were seen at 243 ppm. The NOAEL was 27 ppm, equal to
2-3 mg/kg bw/day.
There were two additional delayed neurotoxicity tests in hens.
In the first, atropine and oxime antidotes were used with a dose of
triazophos about 7 times the unprotected LD50 of 7.5 mg/kg bw. In the
group treated with triazophos, high mortality was seen and only 4 hens
survived to termination. Among these 4 hens, signs of ataxia were
seen in 2 hens and histological lesions were seen in the nervous
tissue of 3 animals. In the second study, at lower doses (about twice
the unprotected LD50), triazophos displayed no neurotoxic effects.
A 90-day neurotoxicity study in hens at dietary concentrations of
0, 50, 110 or 250 ppm, was preceded by a 20-day preliminary study. In
the preliminary study, at dietary levels up to 200 ppm, there were no
neurotoxic symptoms and neuropathy target esterase (NTE) activity
remained undisturbed by treatment. Histopathology was not performed.
In the main study, cholinergic signs were seen at the high dose of 250
ppm and one hen (of 10) died on day 76. This hen, and one other,
displayed clinical signs of neurotoxicity. Plasma cholinesterase
activity was markedly reduced at all doses, but NTE activity was not
investigated. Morphological lesions characteristic of neurotoxicity
were reported in the spinal cord and peripheral nerves. The study
report stated that lesions were more severe and seen more frequently
in hens treated with triazophos than in controls. The Meeting
concluded that it was difficult to interpret these histopathology
findings since, most unusually, lesions were frequently seen in the
spinal cord, but very infrequently in the peripheral nerves, of
control animals.
The Meeting reviewed the results of male and female human
volunteer studies previously summarized in the 1982 monograph. A
series of experiments had been conducted, including a three-week trial
with 25 volunteers. The present Meeting agreed with the conclusion of
the 1982 JMPR regarding that trial: a dose of 0.0125 mg/kg bw/day of
triazophos was a minimal effect level with regard to plasma
cholinesterase activity but was without effect on erythrocyte
acetylcholin-esterase.
In view of the uncertainty regarding the potential for triazophos
to cause delayed neurotoxicity, the Meeting extended the temporary
ADI, basing it on the NOAEL in dogs, utilizing a 500-fold safety
factor.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Mouse: 30 ppm in the diet, equal to 4.5 mg/kg bw/day
Rat: 3 ppm in the diet, equal to 0.17 mg/kg bw/day
(long term study)
27 ppm in the diet, equal to 2-3 mg/kg bw/day
(multigeneration study)
Dog: 4 ppm in the diet, equal to 0.12 mg/kg bw/day
Human: 0.0125 mg/kg bw/day
Estimate of temporary acceptable daily intake for humans
0-0.0002 mg/kg bw
Studies without which the determination of a full ADI is
impractical
To be submitted to WHO by 1992:
1. Clarification of the potential for triazophos to cause delayed
neurotoxicity through an acute delayed neurotoxicity study in
hens combined with measurements of acetylcholinesterase and
neuropathy target esterase inhibition in nervous tissue.
2. Submission of ongoing studies, including those on antidotes to
acute poisoning.
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