OXFENDAZOLE
First Draft prepared by
Dr. Radovan Fuchs
Institute for Medical Research and
Occupational Health, University of Zagreb, Yugoslavia
1. EXPLANATION
Oxfendazole is an anthelmintic used for the treatment of
gastrointestinal parasitism in cattle, sheep and horses.
Oxfendazole has not been previously evaluated by the Joint FAOP/WHO
Expert Committee on Food Additives.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Absorption, distribution and excretion
Oxfendazole, fenbendazole and febantel are three metabolically
related anthelmintics. Fenbendazole and oxfendazole are
metabolically interconvertible, and febendazole is a prodrug of them
both. Oxfendazole and fenbendazole both undergo further metabolic
oxidation and carbamate hydrolysis.
Using 14C-oxfendazole it was shown that systemic exposure to
total drug equivalents is the same in rats and calves for equivalent
doses. Systemic exposure in the rat occurs within 24 hours while in
the feeder calf it occurs slowly over 168 hours (Tomlinson et al.,
1986).
Plasma concentration in rats as a function of time after oral
administration of 3H-oxfendazole is the same as after intravenous
administration, indicating complete absorption of the oral dose.
Between 0-12 hours after intravenous injection of 6 mg/kg b.w. of
3H-oxfendazole to rats, the t´ of free extractable material in
the plasma was 360 minutes. In the same experiment, t´ decreased
to 160 minutes during the 12-24 hour interval. The apparent volume
of distribution for the drug, based on chloroform extractable
tritium, was estimated to be 85 ml/rat or 607 ml/kg b.w. (Tomlinson,
1974a).
In rats, the plasma metabolite pool is composed of 29%
oxfendazole, 71% sulfone analogue and 1% thioether analogue. In
calves, although the metabolites are the same as those found in
rats, the plasma metabolite pool consists of 20% oxfendazole, 46%
sulfone analogue and 20% thioether analogue (Tomlinson et al.,
1986).
Oxfendazole is excreted in urine and faeces (Tomlinson, 1974a;
Tomlinson et al., 1986). In rats, recovery of the dose after oral
administration averaged 40-50% within 48 hours (Tomlinson, 1974a).
In calves, 14-20% of the dose was recovered in urine, a considerably
lesser amount, and much more was eliminated via faeces (Tomlinson et
al., 1986). In rats, oxfendazole or its metabolites may be cycled
through the enterohepatic path as many as four times before being
eliminated from the body (Tomlinson, 1974a). Both in rats and in
calves the major residue burden was located in the liver and major
identifiable metabolites were the same (Matin et al., 1977). Of the
residue present in liver, a significant portion cannot be extracted
into organic solvents. At 0.5 hours and 24 hours
post-14C-oxfendazole administration, 41% and 93% respectively of
the residue was protein bound (Tomlinson et al., 1986). Studies in
cattle have shown that besides liver, milk from treated animals
(Tomlinson, 1977) contained oxfendazole, its thioether, its sulfone
and protein bound materials (liver only). The same metabolites were
found in the livers of treated sheep (Tomlinson, 1974b).
A metabolic scheme may be found on page 23.
2.2 Toxicological studies
2.2.1 Acute studies
Table 1. Acute studies on oxfendazole
Species Sex Vehicle LD50 Reference
(mg/kg b.w.)
Mouse M&F distilled water > 6400 Hallesy, 1973
Rat M&F distilled water > 6400 Hallesy, 1973b
Chester & Bidlack,
1987a
Chester & Bidlack,
1987b
Dog F gelatine capsule > 1600 Hallesy, 1973c
Sheep F water > 250 Braemer & Bidlack,
suspension 1976
Cattle M&F water purified > 112.5 Bidlack, 1977
The gastrointestinal tract and bone marrow were the primary
organ systems affected by the drug. Clinical signs, pathologic
changes, and in some cases mortality were seen in rats, dogs, sheep,
and cattle treated with a single high dose of oxfendazole.
2.2.2 Short-term studies
2.2.2.1 Mice
Groups composed of 10 male and 10 female Swiss Webster mice
were fed diets containing 0, 25, 50, 100, or 200 ppm oxfendazole
(equivalent to 0, 3.75, 7.5, 15, or 30 mg/kg b.w./day) for 3 months.
No signs of toxicity were observed in any of the treated groups
(Hallesey & Shott, 1984).
Groups of Swiss Webster mice (5 animals/sex/dose) were fed diet
containing oxfendazole at concentrations of 0, 5000, 10 000, or 50
000 ppm (equivalent to 0, 750, 3000, or 7 500 mg/kg b.w./day) for 1
month. Data concerning clinical observations, body weight gain, food
intake, clinical pathology, gross pathology and histopathology were
recorded. No clinical signs of drug-related toxicity were observed.
Increase of SGOT and SGPT were observed in intermediate and
high-dose females. A dose-related significant increase of the ratio
of liver weight to body weight was found in all treated animals.
Significant increase in liver weight compared to controls was
observed in intermediate and high-dose animals only. The ratio of
testes weight to body weight in males receiving 20 000 and 50 000
ppm of oxfendazole was significantly lower than that in controls.
Histopathological observations included changes in testes of
intermediate and high-dose groups. Those changes were described as
mild to moderately severe hypospermatogenesis with desquamation of
sperm precursors. Hepatocytic vacuolation was a common finding in
all groups of animals, control group included (Hallesy & Bidlack,
1987a).
An additional study on oxfendazole subchronic toxicity was
conducted on Swiss Webster mice. Five groups of animals composed of
5 male and female mice were fed diets containing oxfendazole at
concentrations of 0, 250, 500, 1000, or 2000 ppm (equivalent to 0,
37.5, 75, 150, or 300 mg/kg b.w./day) for 3 months. During the study
there were no clinical signs of toxicity. Body weight and food
intake were not affected by the treatment. Changes attributed to
treatment consisted of increased liver weight in males and females
receiving 1000 or 2000 ppm and in female mice receiving 500 ppm
oxfendazole in diet. Histopathologically, hepatocytic vacuolation
was seen in all mice including controls, although the vacuolation
was more severe in male mice fed diets containing 500, 1000, or 2000
ppm of the drug. Male animals from the highest group dose had
testicular changes described as hypospermatogenesis with sloughing
of sperm precursors (Hallesy & Bidlack, 1987b).
2.2.2.2 Rats
Groups of 5 male and female Sprague-Dawley (COX-SD) rats were
given doses of 0, 5, 20, 80, or 160 mg/kg b.w./day oxfendazole by
gavage for 14 consecutive days. The test material was homogenized in
2% aqueous starch.
Reduction in body weight was observed in animals dosed at
160 mg/kg b.w./day during the first week of treatment, but at the
end of the observation period (28 days) the animals showed normal
weights compared to the controls and other groups. Four out of 5
females of the 160 mg/kg b.w./day group were found dead at times up
to and including the 14th day of the study. At the 80 and 160 mg/kg
b.w./day doses, neutrophil counts were depressed during dosing, but
at the end of the 2-week recovery period the neutrophil levels of
the surviving rats had returned to normal values. Pathology was not
performed on all of the animals in this study and the cause of death
was not ascertained in every rat necropsied (Hallesy et al., 1976a).
Groups of Sprague-Dawley (COX-SD) rats (6 animals/sex/group)
were given doses of 0, 11, 33, or 100 mg/kg b.w./day oxfendazole by
gavage for 14 consecutive days. During the dosing period 4 out of 12
from the high-dose group died. Decreased weight gain was seen in
females of the intermediate-dose group and in males and females from
the high-dose group. Haematology and clinical chemistry were studied
after 2 weeks of treatment. Decreased haemoglobin and haematocrit
levels in females given 100 mg/kg b.w./day, and decreased numbers of
neutrophils in females given 33 or 100 mg/kg b.w./day and in males
given 100 mg/kg b.w./day were seen. No changes in clinical chemistry
values in treated rats were observed when compared to controls.
Decreased terminal body weight for high-dose rats, decrease in
splenic and testicular weight and increased liver weight for
intermediate-dose and high-dose rats were noted. Numerous gross
alterations were noted, which included thymic atrophy, pronounced
hepatic pallor, increased alimentary tract fluids and red-brown foci
in the glandular stomach. Histopathologically, lymphoid atrophy and
inhibition of maturation of bone marrow myeloid and erythroid
elements in intermediate and high-dose rats were observed.
Inhibition of spermatogenesis and inflammatory lesions in lungs of
high-dose animals were also seen. Hepatocytic vacuolation was
observed in some animals of all dose groups (Hallesy et al., 1977b).
In a 3-month study oxfendazole incorporated into the diet at 0,
200, 600, and 2000 ppm was given to Long-Evans rats
(15 rats/sex/dose level). Thirteen rats out of 30 died by the end of
the first week of dosing due to toxic effects. This group was
terminated and an additional two groups receiving 50 and 100 ppm of
oxfendazole in the diet (10 rats/sex/dose level) were placed on
test. The approximate daily intakes of oxfendazole over the period
of the study were 0, 3.8, 7.3, 16.5, and 53.8 mg/kg b.w./day for
males and 0, 3.8, 7.7, 17.2, and 49.9 mg/kg b.w./day for females. By
the end of the study, 24 out of 30 rats receiving 600 ppm of
oxfendazole in feed died. In this group perioral and mandibular
alopecia with encrustation, priapism, and enlarged clitoris were
observed. Elevation of SGPT and SAP levels was observed in the 600
ppm group. SAP was slightly elevated in both sexes of the 200 ppm
group and in females of the 100 ppm group. Hepatocytic hypertrophy,
vacuolation and hepatocytic necrosis were seen in the 600 ppm group.
Other pathological changes consisted of testicular atrophy, splenic
necrosis or atrophy, abscesses and bone marrow hyperplasia or
diffuse atrophy. In the 200 ppm group only slight hepatocytic
hypertrophy was observed. In the 100 and 50 ppm groups no
microscopic changes related to treatment were observed (Killeen &
Rapp, 1974a).
2.2.2.3 Dogs
Groups of 2 male and female beagle dogs were given 0, 11, 33,
or 100 mg/kg b.w./day oxfendazole by gavage for 2 weeks. A slight
decrease in body weight was observed in male dogs given 33 mg/kg
b.w./day and in male and female dogs from the 100 mg/kg b.w./day
group. None of the haematological or plasma chemistry parameters was
affected by the treatment. No meaningful changes were seen in
urinalysis values after 2 weeks of dosing. Histological changes
attributed to oxfendazole treatment were seen in dogs from all
treated groups; reduced myeloid maturation was seen in bone marrow.
Reduction of splenic lymphoid tissue and thymic atrophy were seen in
males but not in females (Hallesy et al., 1976b).
In a second 2-week study on beagle dogs groups of 4 males and
females were given oxfendazole at doses of 0, 3, 6, and 11 mg/kg
b.w./day by gavage. No drug-related effects were seen in the animals
killed after the dosing period (half) or in remaining dogs observed
for 3 weeks after dosing. In this study a different suspension
formulation of oxfendazole was used than that used in the previous
study (Hallesy et al., 1977a).
Groups of 3 male and female beagle dogs were given 0, 1.5, 3.0,
and 6.0 mg/kg b.w./day of oxfendazole orally in hard shell gelatin
capsules for 3 months. No changes related to oxfendazole treatment
were observed in body weight, gross pathology, or histopathology in
any of the groups at the end of the study when the dogs were killed
(Killeen & Rapp, 1974b).
2.2.2.4 Cattle
Hereford heifers and bulls from 6 to 8 months old were used in
the study. Groups consisting of 3 male and female animals were used.
Oxfendazole was injected intraruminally at doses of 0, 4.5, 13.5,
22.5, and 112 mg/kg b.w. Oxfendazole was prepared as a 22.5% drug
suspension. The highest dose (112 mg/kg b.w., corresponding to 25
times intended field use level) was given as a single dose, whereas
the other dose groups were treated 3 times over an 8-day period.
Body weights, haematological and clinical chemistry values were not
altered by the treatment. No treatment-related gross or microscopic
pathological changes were observed. In only one male and one female
animal digestive disturbances described clinically as non-productive
eructation were seen in the highest dose group. The inflammatory
reactions noted at the injection site in all groups, including
control, were attributed to contaminants introduced during
intraruminal injections (Glock et al., 1987).
2.2.3 Long-term/carcinogenicity studies
2.2.3.1 Mice
Fifty CD-1 mice of each sex were randomly assigned to each of
three treatment groups. Oxfendazole was administered in the diet at
concentrations of 100, 300, or 1000 ppm, which was equivalent to
dose levels of 15, 45, or 150 mg/kg b.w./day respectively. A control
group of 100 animals of each sex received the same diet without
oxfendazole. An additional 10 mice of each sex per group were
included for haematological evaluation. The animals were treated for
78 weeks. Clinical observations and presence of palpable masses were
recorded weekly, while body weight and food intake were recorded
weekly for the first 4 months and monthly thereafter. Blood samples
for haematological evaluation were obtained during the 6th and 12th
months of treatment from the designated animals. A complete necropsy
and histopathological examination was performed at study
termination.
No treatment-related effects were noted on clinical condition
or survival. Mean body weights for treated males were often lower
than those for controls during the first year of the study.
High-dose females had significantly higher body weights than
controls during the first year. Food intake was higher for all
treated groups during the first year. No biologically significant
haematological effects were noted. A slightly higher proportion of
high-dose males had malignant neoplasms compared to controls. This
included a higher incidence of broncho-alveolar and hepatocellular
carcinomas. However, the difference was not statistically
significant. In females the proportion of high-dose animals with
either benign or malignant neoplasms was slightly higher than in the
control group, but the difference was not statistically significant.
Increased incidences of hepatocytic hypertrophy and hepatocytic
vacuolation were observed in high-dose animals. Results were highly
significant for hepatocytic hypertrophy in males and hepatocytic
lipid vacuolation in females. The incidence of focal hepatocytic
necrosis was also slightly greater in high-dose mice compared to
controls. No other histopathological changes attributed to
oxfendazole were observed. The NOEL was 300 ppm, equivalent to
45 mg/kg b.w./day (DePass & Bidlack, 1987c).
2.2.3.2 Rats
Four groups consisting of 25 male and female Sprague-Dawley
weanling rats were fed diets containing 0, 10, 30, or 100 ppm
oxfendazole for one year. The daily intake of the drug over the
studied period was equal to 0.65, 2.0, and 6.6 mg/kg b.w./day for
males and 0.76, 2.4, and 7.8 mg/kg b.w./day for females,
respectively. Body weight and food intake were measured weekly for
the first 13 weeks, and monthly thereafter. Clinical observations
and tissue masses were recorded at least weekly. Blood samples for
haematology and serum chemistry evaluations were collected from an
untreated group of 10 males and 10 females prior to the start of the
study and from 10 designated males and females from each of the 4
groups at 4 intervals during the study. Eye examinations were
performed on each animal prior to the first dose and during study in
the 3rd, 6th, 9th and 12th months. Animals that were found dead, in
moribund condition, or killed at study termination received complete
necropsy examinations.
No drug effect was noted on clinical or ophthalmological
condition or on food intake. Increased body weight gain was observed
in the high-dose female group during the first 6 months. In both
sexes a drug-related increase in BUN was seen. Treatment-related
increase in SAP was also observed in treated animals of both sexes.
Changes in creatinine, GOT, cholesterol, triglyceride measurements,
and several haematological parameters were observed several times
during the study. Those changes were not considered to be of
biological importance since their occurrence was inconsistent in
respect to dose levels, time interval and the sex of the animals.
The liver weight of high-dose animals was significantly higher
compared to other groups and in males a slight reduction of
accessory sex organs in high-dose animals was observed.
Histopathological changes were seen in the livers of intermediate-
and high-dose animals and are described as discoloration and
centrilobular hepatocytic lipid vacuolation. Those changes, although
present in all treated animals when compared to control animals,
were not outside the range of physiological values and historical
data of the laboratory. The NOEL in this study was 10 ppm, equal to
0.65 and 0.76 mg/kg b.w./day in males and females, respectively
(DePass & Bidlack, 1987a).
Groups of 50 Sprague-Dawley rats of each sex were fed
oxfendazole-containing diet for at least 105 weeks (2 years). Drug
concentration in food was 10, 30, or 100 ppm. A control group of 100
animals of each sex received the same diet without oxfendazole. Drug
intake was calculated to be, on average, 0.7, 2, or 7 mg/kg b.w./day
for males and 0.9, 2.5, or 8.8 mg/kg b.w./day for females.
A statistically significant decrease in body weight in response
to increasing dose was noted at several intervals, mostly during the
early part of the study. At some intervals, the treated males
appeared to have higher intake of food than the controls. However,
these observations seemed to be biologically insignificant. Tissue
masses were noted across all treatment groups. Approximately 40% of
the control and low-dose females had masses. Intermediate and
high-dose females had approximate tissue mass incidences of 35% and
25%, respectively. In males, there was a 10% incidence in the
control and intermediate-dose and 6% incidence in the high-dose.
There was no treatment-related mortality and the survival times were
not significantly different among the groups, including controls.
There were no treatment-related effects on clinical conditions or
haematology. Oxfendazole at concentrations of up to 100 ppm daily
for 105 weeks did not offer biological or statistical evidence of an
increased incidence of neoplasms. Hepatocellular lipid vacuolation
was present in the livers of intermediate and high-dose animals and
was found to be dose-related. The NOEL in this study was 0.7 mg/kg
b.w./day in males and 0.9 mg/kg b.w./day in females (DePass &
Bidlack, 1987e).
2.2.3.3 Dogs
Four groups composed of 5 male and female beagle dogs were
given 0, 1.5, 4.5, and 13.5 mg/kg b.w./day oxfendazole daily for one
year. A suspension of the drug was administered orally at a dose
volume of 0.1 ml/kg b.w.. Eye examinations, haematology and serum
chemistry assessments were conducted prior to the first dose and
during the study during the 3rd, 6th, 9th, and 12th months of
dosing.
There were no toxic signs or effects on food intake, body
weight, clinical condition, ophthalmological parameters or serum
chemistry. Decreasing trends were observed for erythrocyte count,
haemoglobin, and haematocrit measurements for male dogs at all time
intervals, but the values were within the physiological range. After
12 months of dosing, the animals were killed for pathological
examination. Liver weight to body weight ratios showed a
statistically significant increase in response to increasing dose in
the four groups, but absolute liver weights only slightly exceeded
those of the control animals. No other gross or microscopic changes
which might be related to treatment were observed. The NOEL in this
study was 13.5 mg/kg b.w./day (DePass & Bidlack, 1987b).
2.2.4 Reproduction studies
2.2.4.1 Rats
In a 2-generation study, 30 Sprague-Dawley rats/sex/dose were
given oxfendazole incorporated into feed. The concentration of the
test substance in the diet was 0, 10, 30, or 100 ppm. The females
received the drug 2 weeks prior to cohabitation with treated males
and until the end of the breeding period. Drug intake was calculated
to be in a range of 0.9-1.0, 2.8-3.1, and 2.8-10.4 mg/kg b.w./day
respectively.
No drug effect was noted on the clinical condition, mean body
weight or average daily food intake of treated rats. No drug effect
was noted for incidence of pregnancy, length of gestation, live
litter size or gestation index. The changes attributed to
oxfendazole treatment consisted of increased mean liver weight and
liver weight to body weight ratios, liver pallor and increased
incidence of hepatocytic vacuolation in high-dose females.
High pup mortality from postpartum days 7 to 14 was noticed in
all dose groups of the F1 generation including controls. Male F1
pups born to high-dose dams weighed less at first observation and
had a decreased rate of growth compared to male pups from control
dams. No treatment-related anomalies were seen. Pups from
intermediate- and high-dose litters had liver changes similar to
those found in their parents. No drug-related effects were noted on
live litter size or survival index for second generation litters.
However, the proportion of pregnancies in high-dose dams was
significantly lower than in controls. Liver changes as previously
described were noted in intermediate- and high-dose parents of the
second generation. Initial second generation pup weights were lower
for intermediate and high-dose litters. No gross or microscopic
changes were noted in second generation offspring. The NOEL for this
study was 10 ppm, equal to 0.9 mg/kg b.w./day (DePass & Bidlack,
1987d).
2.2.4.2 Cattle
Three groups consisting of 33 mixed-breed first calf heifers
were estrus-synchronised using fenprostalene and were intraruminally
treated with oxfendazole. The drug was administered prior to
artificial insemination, at weekly intervals from day 14 through day
42 of gestation and at approximately 60-day intervals to the end of
gestation. The dose levels applied were 0, 4.5, and 13.5 mg/kg
b.w./day. Heifers which did not become pregnant were naturally bred
at subsequent estrus periods.
Conception rates, length of gestation, time to become pregnant,
service period and weight gains of heifers during gestation and
lactation were unaffected by oxfendazole treatment. During the study
1 low-dose and 1 high-dose dam, and 2 high-dose calves died.
Pathological changes in those cases suggested that the deaths were
not associated with oxfendazole treatment.
Oxfendazole did not cause anatomic abnormalities, decreased
birth weight or changes in average daily weight gain in calves. The
NOEL in this study was 13.5 mg/kg b.w./day (Miller et al., 1987).
2.2.5 Special studies on genotoxicity (see also Section 2.2.7 in
fenbendazole monograph and 2.2.5.1 in the febantel
monograph)
Table 2. Genotoxicity studies on oxfendazole
Test system Test object Concentration Result Reference
Ames test1 S.typhimurium 0.5-5000 µg/ml Negative Mourot, 1990
TA97a, TA98,
TA100, TA102
1. With and without S9
2.2.6 Special studies on eye and skin irritation
2.2.6.1 Rabbits
Groups of 6 male New Zealand white rabbits had 100 mg
oxfendazole powder instilled into the conjunctival sac of the left
eye. There were no signs of irritation at any time during
observation (Hallesy & Hill, 1977).
In a separate study, oxfendazole as a 2.265% w/v aqueous
suspension was applied into the conjunctival sac of 5 New Zealand
white and 1 Californian rabbit (6 animals) at a dose of 0.1 ml. No
irritation or corneal damage was seen in any of the animals
(Reynolds & James, 1977).
The oxfendazole formulation was applied to intact and abraded
skin of 6 New Zealand white rabbits. The test sites were occluded
for 4 hours. After removal of dressings test sites were scored for
erythema and oedema. Twenty-four and 48 hours after washing the
scoring was repeated. No evidence of erythema or oedema was seen in
any of the rabbits (Hallesy & Hill, 1976).
2.2.6.2 Guinea-pigs
Female Hartley albino guinea-pigs were used in a dermal
sensitization study. The test was performed on 3 groups of animals:
a positive control group (2,4-dinitrofluorobenzene), a vehicle
control group and an oxfendazole-treated group, consisting of 20
animals each. It was found that neither vehicle nor oxfendazole
produced contact sensitization in guinea-pigs (Hallesy & Hill,
1978).
In a separate study, oxfendazole produced no sensitizing
effects and no primary irritation when tested on Dunkin-Hartley
guinea-pigs. In this study dinitrochlorobenzene was used as a
positive control (Harper & James, 1977).
2.2.7 Special studies on teratogenicity (see also Section 2.2.5 of
the monograph on Fenbendazole)
2.2.7.1 Mice
Groups of 25 mated female Swiss Webster (COX.SW) mice were fed
powdered diet containing concentrations of 0, 200, 600, or 2000 ppm
oxfendazole corresponding to 0, 34, 108, or 360 mg/kg b.w./day. The
animals were exposed to the drug from gestation day 6 through day 15
and the females were killed on gestation day 18.
Food intake was not affected among the groups during the
treatment, although the body weight gains for high-dose mice were
less than those for other groups. The diet containing 2000 ppm was
found to be fetotoxic for mice. In this group decreased litter size,
average fetal weight, and mean gestation survival index were
observed. Viable fetuses from this group were found only in 2 out of
22 pregnancies, and most of the fetuses had been resorbed, resulting
in an increase of the mean resorption index (p 0.01). Because of the
small number of fetuses available (3 alive and 1 dead) the
interpretation of probable teratogenic effects was not possible.
The maternal parameters were comparable between the control and
low-dose or intermediate-dose groups. Various external, skeletal,
and visceral changes were observed in fetuses from the control, low-
and intermediate-dose groups. Among the abnormalities, only the
incidence of pelvic cavitation was increased in low- and
intermediate-dose groups compared to controls. The incidence was
found to be 8% in treated animals and 0% among the controls. Since
similar changes with an incidence of 6 to 7% occur in untreated mice
as well (Palmer, 1972), those changes are not of reliable
importance. The NOEL in this study was 600 ppm, corresponding to
108 mg/kg b.w./day (Hallesy et al., 1974a).
2.2.7.2 Rats
Groups of 25 mated female Sprague-Dawley rats were given
oxfendazole by gavage daily at doses of 0, 10, 20, or 60 mg/kg
b.w./day. The treatment lasted from the 6th to 15th days of
pregnancy. On the 20th day of gestation, the females were killed.
Evidence of fetotoxicity characterized by decreased litter size
and fetal weight, a high incidence of total litter resorption, as
well as an increased resorption index and a higher percentage of
male fetuses were seen in the group receiving 60 mg/kg b.w./day.
Maternal parameters for the 10 and 20 mg/kg b.w./day groups were
comparable to the control animals. Fetal changes were observed in
the 20 and 60 mg/kg b.w./day groups and were typical of those
produced by delayed development and included delayed maturation of
ossification centres. The NOEL in this study was 10 mg/kg b.w./day
(Hallesy et al., 1974b).
The potential embryotoxicity of oxfendazole, the principal
metabolite of fenbendazole, was evaluated in Wistar rats. Sexually
mature virgin female Wistar rats were mated with fertile males, to
provide 4 groups of 20 pregnant animals. Dams were evaluated for
presence of sperm and the day on which sperm was detected was
designated gestation day one. Dams in these groups received doses of
0, 5, 6, 7.5, 10, 15, or 20 mg/kg b.w./day oxfendazole via stomach
tube in a 2% starch mucilage vehicle at the rate of 10 ml/kg
b.w./day on gestation days 7-16. Rats were observed daily, and
weighed weekly. Doses were based on the most recent body weight.
Food intake was monitored continuously. All dams were sacrificed on
gestation day 21 and fetuses were delivered by caesarean section.
Each dam received a gross necropsy and organs were weighed. The
uterus was opened and number and placement of live and dead fetuses
and resorptions were determined. Implantation sites and corpora
lutea were counted. The fetuses from the control, 7.5, and
10 mg/kg b.w./day groups were examined externally for abnormalities
and then about 50% were processed for Alizarin red staining to
evaluate skeletal abnormalities and the remainder were processed
with Bouin's solution for evaluation of soft tissue abnormalities.
No treatment-related effects were observed in the dams. A
significant increase in resorptions, and decrease in live fetuses as
well as a reduction in fetal weight was reported for the 20 mg/kg
treatment group. Examination of the control, 7.5, and 10 mg/kg
fetuses revealed no treatment-related malformations (Kramer &
Baeder, 1973).
The teratogenicity of a series of oxfendazole metabolites and
the parent were evaluated using the rat. Only the parent was found
to have teratogenic activity at a dose of 21 mg/kg (Delatour et al.,
1982b).
In the literature, oxfendazole was reported to produce
teratogenic activity when administered orally to rats from day 8
through day 15 of gestation at 15.75 mg/kg b.w./day or on days 12
and 13 at 31.5 mg/kg b.w./day. Increased incidences of external and
skeletal abnormalities were reported accompanied by substantial
embryolethality (12-39%) (Delatour et al., 1977, 1981, 1984).
2.2.7.3 Rabbits
Groups of 15 inseminated New Zealand white rabbits were dosed
orally with 0, 0.025, 0.125, or 0.625 mg/kg b.w./day of oxfendazole
from days 6 to 18 of pregnancy. The animals were killed on day 29 of
gestation.
There was no overt maternal toxicity nor any effect on litter
size, fetal weight, resorption, corpora lutea, gestation survival
index, resorption index or implantation index. Minor changes
including abnormal carpal and tarsal flexion and low incidence of
gall bladder hypoplasia or aplasia were seen in fetuses from treated
animals. Although greater numbers of high-dose fetuses had minor
skeletal variations, the incidence of those changes was not
significantly different from that of the controls. Based upon the
historical control data and current controls those changes were
considered to be spontaneous and not relevant to oxfendazole
treatment. The NOEL was 0.625 mg/kg b.w./day (Thunen et al., 1981).
2.2.7.4 Sheep
Groups of 27-29 estrus-synchronized ewes were treated orally
with oxfendazole on the 12th, 17th or 23rd day of gestation. Two
dose levels were used: 7.5 and 22.5 mg/kg b.w. Double control groups
(water and vehicle) consisting of 12-14 animals were included in the
study. Altogether 248 ewes were used in the experiment. About 24
hours after the first spontaneous deliveries each ewe was given an
intramuscular injection of dexamethasone. All the lambs that died
were submitted to autopsies, while the animals which reached a
commercial weight were examined at the slaughterhouse. It was found
that oxfendazole administered to pregnant ewes on the 12th or 23rd
day was not related to embryotoxic properties regardless of the dose
applied. On the other hand the birth rate was significantly lower in
the group which received 22.5 mg/kg b.w. of the drug at gestation
day 17. Weight of lambs was comparable among all the groups. Clear
evidence of teratogenic activity of oxfendazole was seen in the
group which was treated with 22.5 mg/kg b.w. on day 17 of gestation.
Malformations were seen on backbone, ribs, face and organs. No
effects were observed in animals which received 7.5 mg/kg b.w. at
any time. The NOEL in this study was 7.5 mg/kg b.w. (Delatour,
1976).
In a field study using 5 merino ewes, oxfendazole was given to
the animals on day 17 of gestation in a single oral dose of 10 mg/kg
b.w. No adverse effects were observed in lambs in this study. The
NOEL was 10 mg/kg b.w. (Lloyd, 1978).
Groups of pregnant Clun-Forest ewes were given a single oral
dose of oxfendazole formulated as 2.265% w/v aqueous suspension.
Eight animals per group received the drug on day 14, 17, or 20 of
gestation at a dose of 10 or 15 mg/kg b.w. The control group did not
receive treatment. There were no differences associated with
oxfendazole treatment between the dosed groups and the controls.
Clinical and autopsy examination revealed no oxfendazole-associated
abnormalities among the lambs. The NOEL in this study was 15 mg/kg
b.w. (Piercy et al., 1977).
2.2.7.5 Pigs
In a field study, oxfendazole was given orally to sows during
pregnancy 4 times at 7-day intervals. A control group consisting of
12 animals did not receive any treatment, while 18 animals were
treated with oxfendazole at a dose of 4.5 mg/kg b.w./day and 18
animals received 13.5 mg/kg b.w./day between the 12th and the 37th
days of pregnancy. No clinical signs of toxicity in the pregnant
sows were observed and there were no drug-related anatomical or
behavioural abnormalities in the newborn pigs. The NOEL was
13.5 mg/kg b.w./day (Morgan, 1982).
2.2.7.6 Cattle
Groups of 15 Hereford-Angus heifers were dosed orally with
13.6 mg/kg b.w. of oxfendazole prepared as 2.265% w/v aqueous
suspension. The drug was administered on days 11, 15, 19, 23, 27,
31, 35, and 39 of gestation. Control animals received a placebo
preparation at the same time intervals.
No signs of clinical toxicity were seen after dosing in either
group of animals. All heifers were killed between day 79 and day 104
of gestation and fetuses were examined. No gross abnormalities were
found in any of the fetuses and there were no significant
differences in fetal weight or length among the groups. No
anatomical abnormalities were found in any fetus. The NOEL was
13.6 mg/kg b.w. (Piercy et al., 1978b).
In a separate study 12 pregnant Hereford-Angus heifers were
treated with oxfendazole as described in the previous study. No sign
of anatomical abnormality related to oxfendazole treatment was
found. The NOEL was 13.6 mg/kg b.w. (Piercy et al., 1978a).
2.2.7.7 Horses
A group of 15 mares was bred with stallions which received
single oral doses of 20 mg/kg b.w. of oxfendazole. On day 26
following breeding the mares received a suspension of oxfendazole
orally at a dose of 20 mg/kg b.w. Pregnant mares were re-treated
with the same dose on days 180 and 280 of gestation. Two out of 15
mares required rebreeding at a second heat period. All mares
maintained pregnancy and delivered healthy foals free of any
teratologic effects (Herschler et al., 1979).
2.2.8 Special studies on mode of action of benzimidazoles
In vitro turbidimetric techniques and competitive
colchicine-binding studies demonstrated the inhibitory power of
benzimidazoles on the polymerization of tubulin into microtubules.
The difference in the sensitivity of host and parasites to the
effects of benzimidazoles may be due to difference in the structure
of microtubules in their cells (Davis & Gull, 1983). However, the
selective toxicity of those compounds for parasites is not absolute,
since the toxic effects are observed in mammals as well and are for
the most part antimitotic (reviewed in McKellar & Scott, 1990). The
differences in efficiency between members of this class of drugs
against groups of parasites probably reflects differences in
bioavailability of the drugs within the host animal.
2.3 Observations in man
No information available.
3. COMMENTS
The results of toxicological studies, including pharmacokinetic
studies on rats, cattle, and sheep; carcinogenicity studies on mice
and rats; mutagenicity, embryotoxicity, and teratogenicity studies
on mice, rats, rabbits, sheep, cattle, pigs, and horses; studies on
eye and skin irritation in rabbits and guinea pigs; reproduction
studies on rats; and short-term and long-term studies on mice, rats,
and dogs, were considered by the Committee.
Pharmacokinetic data have demonstrated very good absorption of
orally administered oxfendazole (100% in rats, 77% in cattle, and
85% in sheep). The results showed that, after administration of the
drug, the plasma metabolite pool was composed of oxfendazole,
oxfendazole sulfone, and fenbendazole. There was very little
difference between the various animal species, apart from
quantitative differences in the plasma metabolite pool. Oxfendazole
is excreted in urine and faeces. The compound and its metabolites
can undergo enterohepatic circulation.
The genotoxic potential of the compound was tested in an Ames
test using only four strains of Salmonella typhimurium; this gave
negative results both with and without metabolic activation.
Carcinogenicity studies were performed in mice and rats. Mice
received a diet containing oxfendazole in doses up to 1000 mg/kg
over a period of 78 weeks. Except for hepatocytic lipid vacuolation,
no effects related to oxfendazole treatment were observed. The NOEL
for this study was 300 mg/kg in the diet, equivalent to 45 mg/kg
b.w./day.
In the rat carcinogenicity study, animals received oxfendazole
in the diet at concentrations of up to 100 mg/kg for 2 years. The
only dose-related effect was seen in animals receiving 30 and
100 mg/kg, which showed hepatocellular lipid vacuolation; this was
the earliest sign of compound-related effects seen in the liver in
this study. The NOEL was 10 mg/kg in the diet, equal to 0.7 mg/kg
b.w./day in males and 0.9 mg/kg b.w./day in females.
The Committee noted that two different strains of mice were
used in the range-finding and carcinogenicity studies. It was
concluded, however, that this difference was not of great
significance since Swiss mice were used in both studies. There was
no evidence of any carcinogenic effect in rats. However, the
Committee was of the opinion, based on the range-finding 90-day
study in rats, that higher doses could have been used.
In a two-generation reproduction study in rats in which
oxfendazole was administered in the diet, no effect was observed on
mating behaviour or fertility, maternal behaviour, length of
gestation, live litter size, gestation index (number of
fetuses/female), or survival of offspring. However, the proportion
of pregnancies in the second-generation females receiving 100 mg/kg
was significantly lower than in controls. The NOEL in this study was
10 mg/kg in the diet, equal to 0.9 mg/kg b.w./day.
Oxfendazole did not produce irritation when tested in the
rabbit eye or skin, or sensitization effects in guinea pig skin.
The Committee considered data from embryotoxicity and
teratogenicity studies of oxfendazole conducted on mice, rats,
rabbits, sheep, cattle, pigs, and horses.
A dose of 360 mg/kg b.w./day was fetotoxic in mice. The NOEL in
mice was 108 mg/kg b.w./day.
Results were reported from three teratogenicity studies in
sheep given doses of oxfendazole ranging from 7.5 to 22.5 mg/kg b.w.
on days 12, 14, 17, 20, or 23 of gestation. The sheep fetus was most
susceptible to the induction of teratogenic effects on day 17, when
the NOELs ranged from 7.5 to 15 mg/kg b.w.
A teratogenicity study was performed in New Zealand rabbits at
doses up to 0.625 mg/kg b.w./day administered on days 6-18 of
gestation. No signs of maternal toxicity or effects on reproduction
indices were reported. A number of minor soft tissue and skeletal
changes were seen in fetuses from treated animals, but these were
thought not to be treatment related, and the study gave a NOEL of
0.625 mg/kg b.w./day. While the Committee recognized that rabbits
may be relatively sensitive to benzimidazole-related toxic effects,
it believed that the doses used in this study were not high enough
to enable the teratogenic potential of oxfendazole in the rabbit to
be adequately explored.
4. EVALUATION
A temporary ADI of 0-4 µg/kg b.w. was established for
oxfendazole, based on a NOEL of 0.7 mg/kg b.w./day from the
carcinogenicity study in rats and the use of a safety factor of 200.
The Committee noted that if the NOEL for teratogenicity in
sheep had been used as the basis for establishing the temporary ADI
together with a safety factor of 2000, the value obtained would have
been of the same order as that derived from the carcinogenicity
study in rats.
A temporary ADI was established because of concern that
sufficiently high doses had not been used in the carcinogenicity
study in rats and the teratogenicity study in rabbits and the lack
of genotoxicity data.
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