TERBUFOS
EXPLANATION
First draft prepared by Dr A. Moretto,
University of Padua, Padua, Italy
Terbufos was evaluated at the 1989 Joint Meeting. The
toxicological monograph was inadvertently omitted from the 1989
Evaluations. Therefore, the monograph is included in the 1990
Toxicology Evaluations.
Terbufos has insecticidal properties against a range of soil-
dwelling and above-ground insects. It is formulated as granules which
are incorporated in the soil at planting, or as a subsequent side
dressing. It is registered in many countries for use on a range of
crops including fruits, vegetables, cereals, oilseeds, coffee and
sugar cane. Use rates are usually 0.2-2 kg a.i./ha.
Terbufos was considered for the first time by the 1989 Meeting.
EVALUATION FOR ACCEPTABLE INTAKE
BIOLOGICAL DATA
Biochemical aspects
Terbufos, 14C-labelled at the thiomethyl group, was given (200
µg) by gavage to 16 Royal Hart Wistar male rats weighing 250-280
grams. Three animals were sacrificed 6, 12, 24 or 48 hours after
dosing; four animals were sacrificed 168 hours after dosing. Urine
was collected 6, 12, 24, 48, 72, 96, 120 and 168 hours after dosing
and faeces 12, 48, 72, 96, 120 and 168 hours after dosing. Urinary
excretion of metabolites peaked at 24 hours and then declined with a
t1/2 of 15 hours. Urine and faeces accounted for 83% and 3.5% of
total radioactivity, respectively. Less than 0.5% of total
radioactivity was found in organs at any of the time-points. Parent
compound was less than 1% of total radioactivity (North, 1973).
Toxicological studies
Acute toxicity
Table 1 reports the LD50 values for terbufos as determined in
different studies and animal species.
In addition, experiments to assess the therapeutic effect of
atropine and 2-PAM administration during acute intoxication with
terbufos were performed. Terbufos (89.2% purity) was given to CFY rats
at 2 or 5 times the subcutaneous LD50 (i.e. 9.8 or 24.5 mg/kg bw).
Atropine alone (17.4 mg/kg bw) or in combination with 2-PAM (50 mg/kg
bw) was injected intramuscularly after terbufos administration; the
first injection was given within 1 hour after intoxication. Treatment
with atropine or atropine plus 2-PAM (high-dose group only) was then
repeated according to clinical signs during the following 22 hours.
All rats died within 27 hours except 1 rat treated with 9.8 mg/kg bw
terbufos and 1 rat treated with 9.8 mg/kg bw terbufos plus atropine.
It appears that under these conditions, atropine and atropine plus 2-
PAM give no protection against terbufos (Davies and Collins, 1974b).
In another experiment, terbufos was given to 15 RH Wistar rats at
1.75, 3.5, 7 or 14 mg/kg bw p.o. Five animals were then treated with
atropine (20 mg/kg bw) and 5 with atropine plus 2-PAM (50 mg/kg bw)
p.o. or i.p. 0 to 6 and 24 hours after terbufos administration.
Results show that atropine alone did not increase the LD50 of
terbufos. The combination of atropine plus 2-PAM increased the LD50
from 3.1-4.2 to 6.5-9.5 mg/kg bw (Fischer, 1975).
Table 1: Acute toxicity of terbufos technical
Species Sex Route LD50 LC50 Reference
(mg/kg bw) (mg/l)
Mouse F oral 5.0 -- American Cyanamid
Company, 1972f;
Morici, 1972
Mouse F,M oral 3.5, 9.2 -- American Cyanamid
Company, 1972f;
Morici, 1972
Rat M oral 1.6 -- American Cyanamid
Company, 1972f
Rat, Newton M inhalation -- 0.0061 Hoffman La Roche,
1987
Rat F,M (4 hr exp.) --, 2.67 0.0012 Wheldon, et al., 1974
i.p. 1.24
Rat F,M dermal 7.4, 0.97 -- Wheldon and BenDyke,
1974a
Rat F,M dermal 9.8 -- American Cyanamid
Company, 1975
Rat F,M subcutaneous 4.9 -- Davies and Collins,
injection 1974a
Rabbit F,M oral 1.6 -- Wheldon and BenDyke,
1974b
Rabbit F,M dermal 0.81, 0.93 -- Fischer, 1985
Rabbit M dermal 1.0 -- American Cyanamid
Company, 1972f
Short term studies
Mice
CF1 mice (10 animals/group/sex) were given 0, 1, 4 or 16 ppm of
terbufos (96.7% purity) in the diet for 31 days. At the end of the
treatment 5 animals per group were sacrificed for autopsy. One and six
females from the 1 ppm and 16 ppm groups, respectively, died during
the study. The cause of death was unknown. The appearance and
behaviour of all treated animals were comparable to those of controls.
In the high-dose group there was a markedly reduced body weight gain
(<60% of controls) and a slightly reduced food intake. Mean kidney
weight was reduced (-12%) in females only. ChE activities were not
determined. The mean daily intake of terbufos was (female data in
parenthesis): 0.218 (0.286), 0.911 (0.988), 3.30 (3.70) mg/kg b.w. in
the 1, 4, and 16 ppm groups, respectively. The NOAEL was 4 ppm (equal
to 0.91-0.99 mg/kg b.w.) for 31 days (Morici, 1972).
Rats
RH Wistar rats (10 animals/group/sex) were given 0, 0.125, 0.5,
or 2.0 ppm of terbufos (96.7% purity) in the diet for 31 days. At the
end of the treatment period, 5 animals per group were sacrificed for
autopsy, determination of ChE activity in plasma, RBC and brain, and
haematological tests. The remaining animals were bled the following
day for haematological studies. Ten animals (including 1 female
control) died during the study (5 died of respiratory infection, 5
died for unknown reasons). The appearance, behaviour, body weight
gain, food intake, gross appearance of internal organs and
haematological parameters were not affected by any of the treatments.
In the high-dose group ChE activity in plasma, RBC and brain was
markedly reduced (to 32-72% of control activity) both in males and
females. The mean daily intake of terbufos was (female data in
parenthesis): 0.012 (0.012), 0.069 (0.053), 0.299 (0.212) mg/kg bw in
the 0.125, 0.5, 2.0 ppm groups, respectively. The NOAEL was 0.5 ppm
(equal to 0.05-0.07 mg/kg bw) (Morici, 1972).
In another study, Sprague-Dawley rats (5 animals/group/sex) were
given 0, 0.125, 0.250, 0.5, 1.0, 3.0 or 6.0 ppm of terbufos (90.1%
purity) in the diet for 14 days. Animals were observed twice daily
and weighed weekly. At the end of the treatment period animals were
sacrificed for autopsy. One female of the 6 ppm group died on day 11
and a second one was sacrificed moribund on day 13. Signs of toxicity
were observed in both males and females at the 6 ppm dose level from
day 2 onward and at the 3 ppm dose level from day 4 onward. No toxic
signs were observed in the animals of the remaining groups. Body
weight gain, food intake, and liver and kidney weights were reduced in
the 6 ppm group. In the 3 ppm group only body weight was reduced. In
the 1 ppm group ChE activity in plasma was reduced from day 1 (males)
or 4 (females); it was also reduced on day 4 (males and females) and
7 (females) in the 0.5 ppm group. RBC ChE activity was reduced from
day 4 in the 1 ppm groups and in males of the 0.5 ppm group; females
of the latter dose level had reduced RBC ChE activity on day 4 only.
The mean daily intake of terbufos was equal to: 0.02, 0.04, 0.08,
0.16, 0.49, 0.77 mg/kg bw in the 0.125, 0.250, 0.5, 1.0, 3.0, 6.0 ppm
groups, respectively. The NOAEL for inhibition of RBC ChE activity,
was 0.25 ppm of terbufos in the diet (equal to 0.04 mg/kg bw) for 14
days (Fischer, 1978).
In another study, Sprague-Dawley rats (20 animals/group/sex) were
given 0, 0.125, 0.250, 0.5 or 1.0 ppm of terbufos (90.1% purity) in
the diet for 3 months. Animals were observed twice daily and weighed
weekly. Haematology testing, clinical chemistry analysis and
urinalysis were performed at week 7 and at termination (10
animals/group/sex). Plasma and RBC ChE activities were determined on
day 1, weeks 1 and 2, months 1, 2, and 3 and at termination. At the
end of the treatment period animals were sacrificed for autopsy and
brain ChE activity determination. All animals, except 2 animals in the
mid-dose group which died accidentally, survived the treatment. No
toxic signs were observed in any animals. Body weight gain, food
intake, ophthalmoscopic observations, haematology, clinical chemistry
and urinalysis were comparable in all groups. In the 1 ppm group ChE
activity in plasma was reduced in males from week 1 (23-42%
inhibition) and in females from day 1 (10% inhibition) onward (36-52%
inhibition). RBC and brain ChE activities were not reduced.
Histological analysis did not reveal any treatment-related alteration.
The mean daily intake of terbufos was equal to (female data in
parenthesis): 0.011 (0.012), 0.021 (0.023), 0.041 (0.048), 0.082
(0.095) mg/kg b.w. in the 0.125, 0.250, 0.5, 1.0 ppm groups,
respectively. The NOAEL for inhibition of brain ChE activity was 1.00
ppm (equal to 0.082-0.095 mg/kg bw) (Daly, 1979).
Rabbits
New Zealand white rabbits (4 animals/group/sex) were given 0,
0.004, 0.020 or 0.1 mg/kg bw of terbufos technical or 0.2, 1 or 5
mg/kg b.w. of terbufos granular formulation (15% a.i.) by dermal
application for 5 days/week for 3 weeks. Test compound was dissolved
in corn oil and applied for 6 hours/day. The skin of animals was
observed daily for erythema, eschar formation and edema. Mild to well-
defined erythema was observed in all groups. Six animals of the 5
mg/kg bw group died between days 6 and 20 of treatment. Haematology
testing, clinical chemistry analysis and urinalysis gave similar
results in all groups. At the end of the treatment animals were
sacrificed for autopsy but no treatment-related histopathological
alterations were observed. Body weight gain, food intake and behaviour
were not affected by any of the treatments. The NOAEL for terbufos
technical dermally applied was 0.1 mg/kg bw for 5 days/week for 3
weeks and 1 (0.15 a.i.) mg/kg bw for 5 days/week for 3 weeks for the
15% granular formulation (Kruger and Feinman, 1973).
Dogs
Groups of 8-12 month-old beagle dogs (2 animals/group/sex) were
administered terbufos (96.7% purity) in the diet calculated to give a
dose of 0, 0.01, 0.05, or 0.25 mg/kg bw/day in the diet for 30 days.
The test compound was dissolved in corn oil and added to the diet in
a volume of 0.25 ml/kg bw. At the end of the treatment animals were
sacrificed for autopsy and determination of brain ChE activity. A
blood sample for clinical chemistry was taken 3 days prior to dosing,
2 weeks after beginning of treatment and at termination. All dogs
survived the treatment without alteration in appearance and behaviour.
Haematological parameters (excluding ChE activities) were not affected
and no gross lesions were seen at autopsy in any animal. Body weight
gain was significantly reduced in the animals of the 0.25 mg/kg bw
group. RBC ChE activity was significantly reduced at 2 weeks and at
termination in the high-dose group and in the 0.05 and 0.25 mg/kg b.w.
groups at termination. Plasma ChE activity was significantly reduced
in the 0.05 and 0.25 mg/kg bw groups at 2 weeks and in all treated
groups at termination. At termination, brain ChE activity was reduced
in the high dose-group only (34% of control). The NOAEL for
inhibition of brain ChE activity was 0.05 mg/kg bw/day (Morici, 1972).
In another study, beagle dogs (4 animals/group/sex) were given 0,
0.0025, 0.010, or 0.040 mg/kg bw/day of terbufos (purity not
reported) 6 days/week for 6 months. At the end of the treatment,
animals were sacrificed for autopsy and determination of brain ChE
activity. A blood sample for clinical chemistry was taken 3 days
prior to dosing, 2 weeks after beginning of treatment and at
termination. All dogs survived the treatment without alteration in
appearance and behaviour. One control animal died of volvulus of the
colon. Haematological parameters and urinalysis were not affected.
Body and organ weights were not affected and no gross lesions were
seen at autopsy in any animal. Plasma ChE activity was inhibited by
26% and 31% in mid and high- dose groups, respectively; RBC ChE
activity was not significant reduced in the high-dose group. No effect
was seen on brain ChE activity. The NOAEL was 0.040 mg/kg bw (the
highest dose tested) (Morgareidge, 1973).
A study was undertaken to establish whether a 6 day/week as
compared to a 7 days/week dosing regimen could influence the outcome
of the previous study. Purebred beagle dogs were given 0.05 mg/kg bw
of terbufos (88% purity) by gavage for 6 or 7 days/week for 4 weeks.
RBC ChE activity was never significantly affected while plasma ChE
activity was reduced on days 7, 21 and 28 of treatment in the 7
days/week group but not in the 6 days/week group: it should be noted
that on those days animals of the latter group were not given terbufos
(Berger, 1977).
In a one-year study, purebred beagle dogs were orally given 0,
0.015, 0.06, 0.24 or 0.48 mg/kg bw/day of terbufos (89.6% purity).
Because of high toxicity, starting from week 7 the high dose was
reduced to 0.12 mg/kg bw and from week 8 the 0.24 mg/kg bw dose was
reduced to 0.09 mg/kg bw. There was a dosing error during weeks 3 and
4 when the 0.015 and 0.06 mg/kg bw dose animals received 5.2% of the
intended dose. Animals were observed twice daily for mortality and
clinical signs. Body weight and food consumption were determined
weekly. Haematological, blood biochemical and urinalysis parameters
were determined twice during pretest period, at months 3 and 6 and at
termination. At termination, animals were sacrificed for gross
pathology, determination of organ weights and of brain ChE activity.
At the 0.24 and 0.48 mg/kg bw doses animals showed clinical signs
consistent with AChE inhibition (salivation, tremor, vomiting,
convulsions). At week 6 one male and one female of the high dose
group died; at week 7 one female of the 0.24 mg/kg bw dose died, and
at week 31 one female of the high dose group was sacrificed moribund
with a prolapsed vagina. Body weight was reduced in the high dose
group before reduction of the dose; it was comparable to control at
termination. Males of the 0.24 mg/kg bw also had reduced body weight
before reduction of the dose. Food consumption was also reduced during
the 0.24 and 0.48 mg/kg bw/day dosing regimen. Haematological, blood
chemistry (excluding ChE activities) and urinalysis parameters and
organ weights at termination were not significantly altered by any of
the treatments. No treatment-related gross pathology alterations were
found. Plasma ChE activity was reduced in all groups in a dose-
dependent manner: it was 55-62% and 26-38% of the control values in
the low and high dose groups, respectively. RBC ChE activity was not
significantly affected in the 0.015 and 0.06 mg/kg dose groups. It was
reduced to 81-84% and 72-82% of control values in male and females,
respectively, of the 0.09 mg/kg bw group. A higher inhibition was
found in the 0.12 mg/kg dose group where activity was 81-84% and 65-
79% of controls in males and females, respectively. The high intra-
and inter-individual variability of brain (cerebrum and cerebellum)
ChE activities, prevented the establishment of an NOAEL for this
parameter. The NOAEL for inhibition of RBC ChE activity, was 0.06
mg/kg bw/day of terbufos (Shellenberger and Billups, 1986).
A 28-day oral toxicity study was undertaken to establish a NOEL
for plasma ChE activity. Terbufos (89.6% purity) was given to beagle
dogs (n = 4/group/sex, except high dose group where n = 2) at levels
of 0, 1.25, 5.0 or 15.0 µg/kg bw/day. No clinical signs were observed.
Brain and RBC ChE activities were not affected. Plasma ChE activity
was slightly reduced in the 5.0 µg/kg dose group; it was reduced to
60-65% of control values in the 15 µg/kg dose group. It must be
pointed out that a great discrepancy was found in brain ChE activity
between controls of this study and that of the one-year study: in the
latter, activities were 191-200 U/g in the cerebrum and 445-536 U/g in
the cerebellum, while in the 28-day study the activities were 0.816-
0.862 U/g and 2.575-3.131 U/g, respectively (Shellenberger and Smith,
1987).
Sheep
Groups of 3 sheep were given 0, 0.01, 0.10, or 1.00 ppm of
terbufos (89.8% purity) in the diet for 42 days. At the end of the
treatment animals were sacrificed for autopsy and determination of
brain ChE activity. A blood sample for haematology and clinical
chemistry was taken prior to dosing, 3 weeks after beginning of
treatment and at termination. All animals survived the treatment
without alteration in appearance and behaviour. No haematological
parameters, including RBC ChE activity, which was measured on days 1,
3, 7, 14, 21 and 42, nor urinalysis, were affected. The mean daily
intake of terbufos was: 0.0003, 0.0023, 0.0245 mg/kg bw in the 0.01,
0.1, 1.0 ppm groups, respectively. The NOAEL for inhibition of RBC
ChE activity was 1 ppm of terbufos in the diet, equal to 0.0245 mg/kg
bw/day of terbufos for 42 days (Garces, 1977).
Calves
Groups of 3 Holstein calves were orally given 0.05 or 0.10 mg/kg
bw of terbufos (97.9% purity) for 7 days. RBC ChE activity, measured
on days 1, 3, 5 and 7 of treatment, was found significantly reduced as
compared to pretreatment on days 5 and 7 (by 25 and 31%,
respectively). The dose of 0.05 mg/kg bw had no effect on RBC ChE
activity (Wang, 1972).
Long-term/carcinogenicity studies
Rats
Long-Evans rats (60 animals/group/sex) were given terbufos in
the diet at concentrations of 0, 0.25, 1, 2 ppm for 24 months. Diets
were prepared from pre-mix containing 100 ppm of a.i. From day 35 the
dose of 2 ppm was increased to 4 ppm and from day 77 to 8 ppm; for
females it was decreased to 4 ppm from day 105 onward. Toxicity
following chronic administration and carcinogenic potential of
terbufos were evaluated. At 3 months, 10 animals/sex/group and 10
controls/sex were sacrificed, necropsies and histological examinations
were performed.
The animals in the high dose group had a lower food consumption
and a reduced (about 20-28%) body weight. Clinical signs of
cholinesterase inhibition were observed in females of the high-dose
group; the signs decreased in severity from month 4 and disappeared
from month 18. Few females in the mid-dose group had clinical signs
during months 5 and 6. Only 8 males of the high-dose group displayed
clinical signs during the last 3 months of treatment. Mortality was
(males-females) 38-33%, 48-26%, 57-33%, 62-60% in the control, low-,
mid-, high-dose groups, respectively. Haematological and clinical
chemistry parameters did not show any treatment-related alteration.
Plasma and RBC ChE activities were significantly decreased in mid- and
high-dose groups and randomly in the low-dose groups. Brain ChE
activity was reduced in the high dose groups (in males by 62%, in
females by 58%) and in females of the mid-dose group (by 10%). In the
high dose groups, liver, kidney (males), heart (males) and thyroid
weights were reduced. A higher incidence of exophthalmos was found in
females of the high dose group during month 4. Terminal
ophthalmoscopic examination revealed an increased incidence of corneal
scars in the high-dose females possibly related to the higher
incidence of exophthalmos observed during month 4. Histological
examination revealed an increased incidence of bronchopneumonia,
foreign body granulomas and gastric ulcerations in the high-dose
animals. The incidence of neoplasms was not increased. The mean daily
intake of terbufos was (males-females): 0.010-0.013, 0.043-0.054,
0.329-0.215 mg/kg bw in the 0.01, 0.10, 2.00-8.00 ppm groups,
respectively. The NOAEL for inhibition of brain ChE activity was 0.25
ppm of terbufos in the diet (equal to 0.010-0.013 mg/kg bw) (Rapp,
1974; McConnell, 1983).
In a second study, Sprague-Dawley CD rats (30 animals/sex/group)
were given terbufos (89.6% purity) in the diet at concentrations of 0,
0.125, 0.5 or 1 ppm for one year.
No statistically significant effect was seen on body weight, body
weight gain and food consumption. Haematological parameters and
urinalysis (performed in 10 animals/group/sex at 3, 6 and 12 months)
were not altered by any treatment. A higher number of females of the
high dose group had chromodacryorrhoea (7/29), excess lachrymation
(6/29) and alopecia (10/29) as compared to controls (2/29, 2/29 and
4/29, respectively). Mortality was (males-females) 1-1, 0-0, 2-1, 0-0
in the control, low-, mid-, high-dose groups, respectively. Plasma ChE
activity (determined on week 6, months 3, 6 and 12) was significantly
decreased in high-dose males from month 6 onward (-25/29%) and in
females throughout the test period (-33/51%). RBC ChE activity was not
affected by any treatment. Brain ChE activity was significantly
reduced (-8/10%) in the high dose groups. In the high dose groups,
kidney (females) and testes weights were reduced. Ophthalmoscopic
examination did not reveal any treatment-related alteration. Increased
incidences of non-neoplastic or neoplastic alterations were not found.
The mean daily intake of terbufos was (males-females): 0.007-0.009,
0.028-0.036, 0.055-0.071 mg/kg bw in the 0.125, 0.50, 1.00 ppm groups,
respectively. The NOAEL was 0.50 ppm of terbufos in the diet (equal to
0.028-0.036 mg/kg bw) (Daly and Knezevich, 1987).
Mice
CD-1 mice (65 animals/sex/group) were given terbufos (purity
89.6%) in the diet at concentrations of 0, 3, 6, 12 ppm (a.i.) for 18
months. Animals were observed twice daily for toxicity signs and
weighed weekly until week 13, every two weeks until week 26 and every
4 weeks afterwards. Haematological parameters were determined for 10
animals/group/sex after 12 months and at termination. Ten
animals/group/sex were sacrificed during week 53 and the survivors
were sacrificed at termination for gross observation and microscopic
examination. Animals found dead or sacrificed moribund were examined
for gross pathological and histological alterations. Mortality was
(males-females) 10.7-23.1%, 7.6-10.7%, 4.6-18.5%, 21.5-27.7% in the
control, low-, mid-, high-dose groups, respectively. Body weight gain
was reduced in males (-10%) and females (-20%) of the high dose
group. Transient decrease in body weight was observed in mid-dose
groups during the first 5 weeks of treatment. Food consumption was
random and slightly depressed in high dose animals but not in the
other treatment groups. Haematological parameters and urinalysis were
not altered by any treatment. No treatment-related clinical signs were
observed. No increased incidence of non-neoplastic or neoplastic
alterations was found. The NOAEL was 6 ppm in the diet (equivalent to
0.9 mg/kg bw/day) (Silverman et al., 1986).
Reproduction Study
Three successive generations of Long-Evans rats were given either
0, 0.25 or 1.00 ppm (a.i.) of terbufos technical in the diet. Diets
were prepared from a pre-mix containing 100 ppm of a.i.. The 3
generations of parents were mated once, twice and once, respectively.
F0 generation parents were mated once after a 60-day growth
period; selected offspring from this mating were chosen to became F1
parents. F1 parents were mated twice after an 80-day growth period
with a 10-day resting period between matings; selected offspring (10
males and 20 females) from the first mating (F2a) were chosen to
become F2 parents; offspring of the second mating (F2b) were
discarded at weaning. F2 parents were discarded after gross
necropsy at weaning. The F0, F1 and F2 parents were discarded
after their offspring were weaned. Compound was administered to
weanling F0 generation rats and continued uninterrupted throughout
the successive generations.
No compound-related effect was seen on mortality, mating
performance, pregnancy or fertility rate. Mean body weights were
increased in both sexes of treated groups (except in the females of
the F0 generation) as compared to control for most weeks. The mean
food consumption of the high dose F2 males and F1 and F2 females
were above control values for most weeks. During gestation and
lactation increased body weight and body weight gains were observed in
the F0 and F1 females of both treated groups. The F2 females
showed an increase only for the gestation period in the high-dose
group.
F1 parents were mated twice because survival rates and weight
gains of F2a offspring of all groups were not within normal values.
Mean number of pups born alive and dead was not affected by any
treatment. Postnatal offspring survival indices showed sporadic, non
dose-related differences from control data. An increase of the
percentage of litters with offspring deaths was observed in the high-
dose groups for all matings and generations (statistically significant
in F2a generation only) when compared to the respective control
groups. No differences (except in the high-dose F1 generation,
during mating period) were observed in the weight of offspring. No
compound-related effect was observed at necropsy. The compound intake
was found to be 0.016-0.035 and 0.067-0.142 mg/kg bw/day in the low
and high-dose groups, respectively. The NOAEL was 0.25 ppm in the
diet, equal to 0.016-0.035 mg/kg bw (Smith, 1973).
Special studies on embryo/fetotoxicity
Rats
Groups (n = 24-25) of mated female rats (Charles River COBS CD)
were given daily oral doses (0, 0.05, 0.10 or 0.20 mg/kg bw) of
terbufos (87.8% purity) dissolved in corn oil from day 6 through 15
of gestation (day 0 of gestation was determined by the presence of
copulatory plug or sperm in vaginal smear). These doses were based on
the results of a range-finding study where all dams treated with 0.40
mg/kg bw or more died or were sacrificed moribund (Rodwell, 1984).
Animals were observed routinely for physical appearance, behaviour and
body weight gain. At day 20 of gestation pups were delivered by
caesarean section. Fetuses were weighed, sexed, inspected for external
abnormalities and examined for visceral and bone malformations.
No alteration of physical appearance and behaviour was observed
in any group. All animals survived until the caesarean section. Body
weight gain between gestation days 9 and 12 was reduced in the mid-
dose group: this is attributed to random occurrence. A slight but not
statistically significant reduction of body weight gain was
demonstrated in the 0.10 and 0.20 mg/kg bw dose groups (-7% and -10%
as compared to controls, respectively) during gestation days 12-16.
Body weight gain remained slightly (6-7%), but not significantly
reduced after treatment (gestation days 16-20). A slight decrease, not
significant and not dose-related, in the mean number of viable fetuses
was observed in the 0.10 (13.7) and 0.20 (13.6) mg/kg bw dose groups
(control=15.0) as a result of an increased post-implantation loss in
these groups as compared to controls. Sex ratio and fetal body weights
were similar in all groups. No treatment-related visceral or skeletal
abnormalities were observed. It is concluded that there was no
evidence of embryotoxicity or teratogenicity at any of the doses used
(Rodwell, 1985).
Rabbits
Groups (n = 18) of artificially inseminated female rabbits (New
Zealand White strain) were given daily doses (0, 0.1, 0.2, 0.4 mg/kg
bw) of terbufos (87.8% purity) by gavage from day 7 through 19 of
gestation. Doses were corrected for purity. These doses were based on
the results of a range-finding study where all dams treated with 2.0
or 4.0 mg/kg b.w. and 80% of dams treated with 0.7 mg/kg b.w. died
(MacKenzie, 1984). Animals were observed routinely for physical
appearance, behaviour and body weight gain. At day 29 of gestation
pups were delivered by caesarean section. Fetuses were weighed, sexed,
inspected for external abnormalities and examined for visceral and
bone malformations.
No alteration of physical appearance and behaviour was observed
in any group except single episodes of lachrymation, diarrhoea,
anorexia or lethargy. Mortality was 0, 11, 0, 33% in control, low-,
mid- and high-dose groups respectively. In the high-dose group,
however, 2 of the 6 deaths were due to gavage error and 2 females
showing signs of aborting were sacrificed. No difference in body
weight gain was observed. No dead fetuses were observed. Number of
corpora lutea, implants and resorbed fetuses, implantation efficiency,
sex ratio and fetal body weights were similar in all groups. No
treatment-related visceral or skeletal abnormalities were observed.
Delayed skeletal development (full unilateral rib, chain fusion of
sternebrae) was seen in the high-dose group. However, only 10 of the
18 females of the mid-dose group were pregnant and 3 of them had
resorptions only; therefore, only 7 litters were observed. In the
high-dose group only 10 litters were observed (6 deaths and 2 non-
pregnant animals). It is concluded that there was no evidence of
teratogenicity at any of the doses used. The dose of 0.40 mg/kg bw had
toxic effect to dams and fetuses, the latter possibly related to
maternal toxicity (MacKenzie, 1985).
Because of the mortality in the high-dose group and the low
pregnancy rate in the mid-dose group, the study was repeated.
Groups (n = 17) of artificially inseminated female rabbits (New
Zealand White strain) were given daily doses (0, 0.05, 0.10, 0.25,
0.50 mg/kg bw) of terbufos (89.6% purity) by gavage from day 7
through 19 of gestation. Doses were corrected for purity. Animals were
observed routinely for physical appearance, behaviour and body weight
gain. At day 29 of gestation pups were delivered by caesarean section.
Fetuses were weighed, sexed, inspected for external abnormalities and
examined for visceral and bone malformations.
An increased incidence of soft-liquid faeces was observed in the
high dose group. All animals survived until termination. One dam in
the 0.1 mg/kg bw and one in the 0.5 mg/kg dose groups aborted. There
was a reduced but not statistically significant body weight gain in
the 0.25 and 0.5 mg/kg bw groups; between gestation days 16 and 20
there was a slight body weight loss (-0.01 kg) in the high dose group.
No effect on food consumption was observed. Pregnancy rates were 94,
71, 82, 77 and 88% in the 0, 0.05, 0.10, 0.25 and 0.50 mg/kg bw
groups, respectively. At necropsy, reddened areas in the fundic region
of the stomach were observed in two high-dose dams. Numbers of corpora
lutea, implants and live and resorbed fetuses, implantation efficiency
and sex ratio were similar in all groups. Fetal body weight was
slightly but not significantly reduced (- 5%) in the high dose group.
No treatment-related visceral or skeletal abnormalities were observed.
It is concluded that there was no evidence of teratogenicity at any
of the doses used. The dose of 0.50 mg/kg bw had toxic effect to dams
and possibly to fetuses. The NOAEL was 0.2 mg/kg bw/day (Hoberman,
1988).
Special studies on genotoxicity
Terbufos was variably active in a range of in vitro assays.
In vivo, however, terbufos was inactive. Results are summarized in
table 2.
Special studies on metabolites
Mice
Acute oral toxicity of some metabolites of terbufos was studied
in female mice. Data are reported in table 3.
Dogs
Groups of male beagle dogs (n = 4 for treated groups, n = 6 for
controls) were given daily oral doses of terbufos or its metabolites
for 14 days as follows: terbufos (89.6% purity) 2.5 or 250 µg
(a.i.)/kg bw, terbufos sulfoxide (metabolite no. 16) (92% purity) 5.0,
15.0, 62.5 or 250 µg (a.i.)/kg bw or terbufos sulfone (metabolite no.
22) (90% purity) 15.0, 62.5, 250 or 1000 µg (a.i.)/kg bw. Animals were
observed for body weight, food intake, mortality, clinical signs,
plasma and RBC ChE activities. At termination ChE activity was
determined in brain (cerebrum and cerebellum) and gross necropsy was
performed. Two dogs receiving terbufos sulfone (1000 µg/kg bw) died
during the study and one was sacrificed moribund. Two of these dogs
had intussusception of the small intestine. Animals of all high dose
groups had reduced body weight at termination and reduced food intake
as compared to controls, with no body weight gain during the treatment
period. At gross necropsy, alteration of gastro-intestinal tract
(dark, red areas, intussuseptions, prolapsed anus) were seen only in
the high dose of terbufos sulfone and terbufos sulfoxide groups.
Plasma ChE activity was found inhibited in all terbufos treatment
groups: activity was 75-82% and 24-27% of pretest values in the low
and high dose groups, respectively. RBC ChE activity was inhibited in
all high dose groups (7-20% of pretest values) and in the 62.5 µg/kg
terbufos sulfoxide at termination (76% of pretest value). Cerebrum ChE
activity was inhibited in all high dose groups (38-63% of control
values); activities of cerebellum ChE had a high variability which
Table 2. Results of genotoxicity assays on terbufos
Test system Test object Concentration Purity Results Reference
In vitro
Ames test S. Typhimurium 10-1000 µg/plate 88.0% negative1 Allen, 1977
TA-98, 100,
1535, 1537
Bacterial WP-2uvrA 10-1000 µg/plate 88.0% negative Allen, 1977
mutation2 (with
and without
activation
Ames test1 S. Typhimurium 50-5000 µg/plate 89.6% negative Allen, 1985
TA-98, 100,
1535, 1537,
1538
Bacterial WP-2uvrA 10 µg/plate 89.6% negative Allen, 1985
mutation2 (with
and without
activation)
Gene mutation Chinese Hamster 10-75 µg/ml 87.8% negative Allen and Johnson
and (HGPRT-test) ovary 1983
in vitro (with and
without activation3)
Chromosomal Chinese Hamster 2.5-25 nl/ml 87.8% negative Thilagar, 1983
aberration in vitro ovary
(with and without
activation)
In vivo
DNA repair5 Rat hepatocytes 0.33-33.3 87.8% negative Godek, 1983
Dominant Rats (male Crl: CD 0.1-0.4 mg/kg 89.6% negative MacKenzie, 1985
lethal test (SD) BR) p.o. for 5 days
Cytogenetic Sprague-Dawley 0.2-1.8 mg/kg 89.6% negative Putman, 1986
assay in vivo Rat i.p. bone
marrow
Table 2 (continued)
1 positive controls (2-aminofluorene, N-methyl-N'-nitro-N-nitrosoguanidine, 2-aminoacridine)
yielded expected positive results.
2 positive controls (N-methyl-N'-nitro-N-nitrosoguanidine) yielded expected positive results.
3 positive controls (ethyl methane sulfonate, 7,12-dimethylbenz(a)-anthracene)
yielded expected positive results.
4 positive controls (cyclophosphamide, triethylenemelamine) yielded expected positive results
5 positive controls (2-acetoaminofluorene) yielded expected positive results.
6 positive controls (triethylenemelamine) yielded expected positive results.
7 reduced number of viable implants at high-dose at weeks 7 and 9
Table 3: Acute oral toxicity of some metabolites of terbufos on female mice
Chemical name LD50 Reference
(mg/kg)
Phosphorothioic acid, S-(tert.- 1.1 American Cyanamid
butylsulfinyl)methyl O,O-diethyl ester Company, 1972a
Phosphorodithioic acid, S-(Tert.- 3.4 American Cyanamid
butylsulfinyl)methyl O,O-diethyl ester Company, 1972b
Phosphorothioic acid, S-(tert.- 3.4 American Cyanamid
butylsulfonyl)methyl O,O-diethyl ester Company, 1972c
Phosphorodithioic acid, S-(Tert.- 14.0 American Cyanamid
butylsulfonyl)methyl O,O-diethyl ester Company, 1972d
Phosphorothioic acid, S-(tert.- 2.2 American Cyanamid
butylthio)methyl O,O-diethyl ester Company
Methane, Bis(tert.-butylsulfonyl) 3670 American Cyanamid
Company, 1973a
Methane, (tert.-butylsulfinyl) >2500 American Cyanamid
(methylsulfinyl) 1973b
prevented any interpretation of the data. The NOAEL for inhibition of
brain (cerebrum) ChE activity, was found to be 2.5, 62.5 and 250 µg/kg
bw/day for terbufos, terbufos sulfoxide and terbufos sulfone,
respectively (Bailey, 1988).
Special study on delayed neurotoxicity
Adult hens (n = 10) were given two doses of 40 mg/kg bw of
terbufos (96.7% purity) by gavage. The second dose was given 26 days
after the first one. This dose was chosen based on an LD50 of 43.5
mg/kg bw. Positive control animals (n=10) received tri-ortho-
cresylphosphate (TOCP) 500 mg/kg bw p.o. Animals were pretreated with
atropine 10 mg/kg b.w. i.m. 10-15 min before the second dose of
terbufos. Animals were observed daily for clinical signs and motility.
Hens treated with terbufos had signs of toxicity which lasted no
longer than 72 hours.
Three hens died after terbufos treatment (2 within 24 hours after
treatment, 1 on day 12). One control animal died on day 19. TOCP-
treated hens showed locomotor impairment beginning day 19, 3 died on
day 26, 2 on day 28 and 1 on day 29. TOCP-treated animals received a
second dose by mistake on day 26 and were sacrificed on day 29,
controls and terbufos-treated hens were sacrificed, asymptomatic, on
day 47. Histological examination of TOCP-treated animals showed
moderate axonal degeneration in lumbosacral spinal cord. No
histological examination was performed in terbufos treated animals.
Terbufos did not cause signs of delayed neurotoxicity in hens at the
LD50 level (Smith, 1972).
COMMENTS
Terbufos is rapidly degraded to metabolites with similar or lower
toxicity than the parent compound. Excretion is mainly in the urine.
In a one year dietary study in rats increased mortality was not
evident at any of the doses used (up to 1 ppm). Slight signs of
toxicity were evident at the 1 ppm level together with a slight, but
statistically-significant, inhibition of brain ChE activity. No
increased incidence of neoplastic lesions was evident. Based on
inhibition of brain ChE activity, the NOAEL was 0.5 ppm in the diet
(equal to 0.028 mg/kg bw/day).
In a one year study in dogs, signs of ChE inhibition were seen
following treatment with doses higher than 0.12 mg/kg bw/day given
orally. Doses up to and including 0.06 mg/kg bw/day did not affect
erythrocyte ChE. The NOAEL for inhibition of erythrocyte ChE was 0.06
mg/kg bw/day.
In a carcinogenicity study in mice, feeding 12 ppm caused
toxicity: reduced body-weight gain and a slight increase in mortality
(ChE activity was not measured) without an increased incidence of
neoplastic lesions. The NOAEL was 6 ppm in the diet (equivalent to
0.9 mg/kg bw/day).
In a two year feeding study in rats, the following were observed
at 1 ppm: increased mortality in males, reduced brain (females) and
erythrocyte (both sexes) ChE activities; at 2-8 ppm: signs of ChE
inhibition, increased incidences of bronchopneumonia, gastric
ulceration and exophthalmos, increased mortality and reduced organ
weights. Terbufos was not found to be carcinogenic in this study.
The NOAEL was 0.25 ppm in the diet (equal to 0.01 mg/kg bw/day).
In a 2-generation, 2 litters per generation reproduction study in
rats, an increase in the percentage of litters with deaths of the
offspring was observed at 1 ppm. The NOAEL was 0.25 ppm in the diet
(equal to 0.016 mg/kg bw/day).
No evidence of embryo/fetotoxicity was found in rats given doses
up to and including 0.20 mg/kg bw/day, whereas all dams treated with
0.40 mg/kg bw/day or more died or were sacrificed moribund. Terbufos
was not found to be teratogenic in rabbits when given at doses up to
and including 0.5 mg/kg bw/day, which was toxic to the dams.
Terbufos did not cause signs of delayed neurotoxicity in hens when
given at a dose level about the LD50.
After reviewing all available in vitro and in vivo tests,
the Meeting concluded that there was no evidence of genotoxicity.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Mouse: 6 ppm in the diet, equivalent to 0.9 mg/kg bw/day (ChE
activity not measured)
Rat: 0.25 ppm in the diet, equal to 0.016 mg/kg bw/day
Dog: 0.06 mg/kg bw/day
Estimate of acceptable daily intake for humans
0-0.0002 mg/kg bw
Studies which will provide information valuable to
the continued evaluation of the compound
Observations in humans.
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See Also:
Toxicological Abbreviations
Terbufos (ICSC)
Terbufos (JMPR Evaluations 2003 Part II Toxicological)