MOXIDECTIN
First draft prepared by
Dr K. Woodward, Veterinary Medicines Directorate,
Ministry of Agriculture, Fisheries and Food, Addlestone,
Surrey, England
Explanation
Biological data
Biochemical aspects
Absorption, distribution, and excretion
Biotransformation
Toxicological studies
Acute toxicity studies
Short-term toxicity studies
Long-term toxicity/carcinogenicity studies
Reproductive toxicity studies
Special studies on embryotoxicity and/or teratogenicity
Special studies on genotoxicity
Special studies on skin irritation
Special studies on eye irritation
Special studies on dermal sensitization
Special studies on pharmacodynamic effects
Comments
Evaluation
References
1. EXPLANATION
Moxidectin had not been previously reviewed by the Committee.
Moxidectin is an antiparasitic drug that is used to control a range of
internal and external parasites in sheep, cattle and deer. Its
chemical structure is shown in Figure 1, page 1.
Moxidectin is synthesized from an intermediate nemadectin,
F-alpha. The constitution of the final product is at least 90%
moxidectin with not more than 4% as F-alpha and related minor
components. The remainder is made up of reaction products from the
production process, with the total content of moxidectin-related
compounds being not greater than 9% (American Cyanamid, 1994a,b).
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Absorption, distribution, and excretion
Pharmacokinetic studies have been conducted with 14C-labelled
moxidectin.
2.1.1.1 Rats
Groups of Sprague-Dawley rats (2/sex/group) were given single
oral doses of 1.5 mg/kg bw 14C-moxidectin in corn oil, and urine,
faeces and expired air were examined at 24, 48 and 72 h post-dosing.
Approximately 92% and 95% of the radioactivity was eliminated in
faeces in males and females, respectively. Less than 0.7% was found in
urine and no radioactivity was detected in expired air (Wu, 1991a).
In a separate study, groups of 5 male and 5 female rats were
given single doses of 1.5 mg/kg bw or 12 mg/kg bw 14C-moxidectin in
corn oil by gavage. A third group of 15 male and 15 female rats was
given oral doses of 1.5 mg/kg bw/day 14C-moxidectin for 7 days. In
animals given single oral doses of moxidectin, 75-80% of the
radioactivity was found in faeces and less than 1% in urine. Residues
of moxidectin were 20 fold higher in fat than in other tissues and in
the 7-day repeat-dose study there was no evidence of bioaccumulation.
The depletion half-lives in fat, muscle and kidney/liver were 11.5,
3.9 and 2.4 days, respectively (Wu, 1991b).
2.1.1.2 Sheep
Eight sheep were given single oral doses of 14C- or
2H-moxidectin at a dose of 0.2 mg/kg bw. The total recovery of the
administered dose was 52% in faeces and less than 1% in urine
(Afzal, 1991a).
After oral, i.v. or s.c. administration of 0.2 mg/kg bw
14C-moxidectin to sheep, the tmax for total 14C in blood after
oral dosing was 9 h with a Cmax of 9 µg/kg moxidectin equivalents.
The elimination half-life was 19.5 h. The latter was similar to the
t1/2 after i.v. administration (26 h). Based on the relative AUCs
for oral and i.v. dose groups, about 23% of the oral dose was
absorbed. With s.c. dosing, the tmax was 8 h with a Cmax of
12 µg/kg equivalents. Average absorption of the s.c. dose was 76%
(Afzal, 1991b).
After oral doses of 0.2 mg/kg bw moxidectin, highest levels of
residues were found in fat at 7, 14 and 21 days post-dosing
(Berger, 1991; DeLay, 1991a).
High levels of moxidectin were found in fat in a 14C study
after oral and s.c. administration to sheep (Wu, 1990a; Wu, 1990b).
Similar results were obtained in a preliminary study where sheep
were given 2 s.c. injections, each of 0.2 mg/kg bw, 10 days apart
(DeLay 1991a,b; DeLay, 1994; Mortimer, 1994).
2.1.1.3 Deer
Twenty red deer were treated with 0.5 mg/kg bw moxidectin as a 5%
pour-on solution. Animals were sacrificed 7, 14, 21 or 28 days after
treatment. Highest levels of residues were found in fat at 7
(126 µg/kg) and 28 days (31 µg/kg), whereas levels in other tissues
were low at day 7 (< 24 µg/kg) (DeLay, 1993).
2.1.1.4 Cattle
A group of 3 cattle received a single s.c. injection of a mixture
of 14C- and 2H-moxidectin at a dose of 0.2 mg/kg bw. Up to 58% of
the dose was recovered in the faeces and 3% or less in urine. The
highest levels of residues were found in fat (900, 635 and 275 µg/kg
at days 7, 14 and 28, respectively), with 109, 77 and 31 µg/kg in
liver, 42, 38 and 13 µg/kg in kidney, and 21, 10 and 4 µg/kg in muscle
at days 7, 14 and 28, respectively. The half-lives for clearance from
tissues were 12-14 days for fat, and 9-12 days for liver, kidney and
muscle (Zulalian, 1991a).
After s.c. administration of 0.2 mg/kg bw 14C-moxidectin to
cattle, the Cmax in serum occurred 8 h after dosing with peak serum
levels of 60 µg/kg moxidectin equivalents. The elimination half-life
was 56 h based on parent moxidectin, and 76 h based on radiolabel.
There were no significant differences when i.v. doses of 0.2 mg/kg bw
were given (Zulalian, 1991b).
Several other studies have also demonstrated that fat is the
target tissue for residues of moxidectin after topical or s.c.
administration (DeLay, 1992a-d; Garces, 1992; Miller 1989; Rooney
1991a). Similar findings were made in calves (Rooney, 1991b), and
relatively high levels have been found at s.c. injection sites
(Rooney, 1991c).
Moxidectin was excreted in the milk of cattle given a s.c.
injection of 0.2 mg/kg bw. Concentrations were 103 µg/kg and 132 µg/kg
at the morning and afternoon milking the day after treatment, 23 µg/kg
on day 7, < 10-12 µg/kg on day 21, and < 10 µg/kg on day 22 after
administration (Garces, 1994; Rooney, 1992).
2.1.2 Biotransformation
2.1.2.1 Rats
After single oral doses of 1.5 or 12 mg/kg bw, or 1.5 mg/kg
bw/day for 7 days, 85-99% was recovered in faeces, the major component
being the parent drug (85%). Six minor metabolites were found in the
liver and faeces. These were the 23-keto derivative, some
monohydroxylated compounds, the C-14 hydroxymethyl and the C-4
hydroxymethyl compounds. These metabo-lites were also noted after
moxidectin was incubated in vitro with rat liver microsomes
(Wu, 1991b).
2.1.2.2 Sheep
In sheep given oral doses of moxidectin, the faecal metabolites
and those found in the liver were qualitatively similar. The major
faecal metabolite was the 9-monohydroxylated derivative of moxidectin,
largely C-29/C-30 (Afzal 1991a).
2.1.2.3 Cattle
Five metabolites were identified in liver, kidney and muscle of
cattle given moxidectin by topical application. Of these, two were
identified as the C-29/C-30 metabolites and the C-14 hydroxymethyl
derivative (Wu, 1992).
In another study, faecal and tissue residues were found to be
qualitatively similar. Six metabolites were identified as
monohydroxylated and dihydroxylated derivatives of moxidectin. The
main component was the C-29/C-30 hydroxymethyl derivative (Zulalian,
1991).
2.2 Toxicological studies
2.2.1 Acute toxicity studies
The results of acute toxicity studies with moxidectin are
summarized in Table 1. Moxidectin was moderately toxic after oral and
i.p. administration to rats and mice. It was somewhat less toxic after
s.c. administration to these species, and of low toxicity to rabbits
after dermal application to intact skin using a 24-h occlusive
dressing.
In the oral studies in mice, the main clinical signs were
decreased activity; surviving animals had fully recovered by day 4. No
gross abnormalities were seen in animals that died or in those killed
at day 14. Similar findings occurred in mice given i.p. doses of
moxidectin.
In rats given oral doses of moxidectin, decreased activity,
prostration, tremors, chromodacryorrhea, decreased respiration,
diarrhoea, hypersensitivity to touch and sound, and epistaxis
occurred. Congestion of the liver, kidneys and lungs were observed in
animals that died, but animals which were sacrificed at the end of the
14-day observation period showed no abnormalities. Similar signs and
effects were noted in rats given i.p. doses of moxidectin.
No overt signs of toxicity were noted in rabbits treated dermally
with moxidectin.
Table 1. Acute toxicity of moxidectin
Species Sex Route LD50 Reference
(mg/kg bw)
Mouse M & F oral 84 Fischer, 1990a
F oral 42 Fischer, 1990a
F oral 50 Fischer, 1990b
M & F i.p. 86 Fischer, 1990b
M & F s.c. 263 Fischer, 1990c
Rat M & F oral 106 Fischer, 1990d
M & F i.p. 394 Fischer, 1990e
M & F s.c. >640 Fischer, 1990f
M & F inhal. 3.28 mg/l Hershman, 1991
(5 h LC50)
Cattle treated with up to 10-fold (2 mg/kg bw) the recommended
therapeutic dose (0.2 mg/kg bw) by s.c. injection showed only mild
depression and ataxia, which soon resolved. No adverse effects were
seen at 3-fold (0.6 mg/kg bw) or 5-fold (1.0 mg/kg bw) the therapeutic
dose (Goodale, 1989; Rooney, 1989a; Rooney 1989b).
Dermal doses of 12.5 mg/kg bw (25 times the therapeutic dose)
were not toxic to cattle (Epperson, 1993). Similar findings were
observed in calves (Kieran & Cobb, 1992).
No adverse effects were seen in lambs given 0.4 mg/kg bw or
1.0 mg/kg bw (2- and 5-fold the therapeutic dose) by oral drench
(Kieran & Cobb, 1991). The NOEL in sheep was 2.0 mg/kg bw (10-fold the
therapeutic dose) after s.c. injection; doses above this produced
salivation, diuresis, tremors, prostration and ataxia (Guerino, 1991).
2.2.2 Short-term toxicity studies
2.2.2.1 Mice
Groups of CD-1 mice (5/sex/group) were given for 28 days 0, 34,
75, 100, 125 or 150 mg/kg dietary moxidectin, equal to 0, 6.9, 18, 23,
24 or 32 mg/kg bw/day.
Signs of toxicity included tremors, hypersensitivity to touch,
and urine-stained fur in mice given 18, 23 and 24 mg/kg bw/day.
Mortality was high in the three highest dose groups (80-100%; all mice
given the highest dietary level died). In the group given 18 mg/kg
bw/day, 1 animal died but there were no deaths in the lowest dose
group.
No effects on haematology were noted in any of the dosed groups
and there were no effects on absolute or relative organ weights. No
gross or microscopic changes were observed in any of the treated
animals. The NOEL in this study was 6.9 mg/kg bw/day (Fischer, 1989a).
2.2.2.2 Rats
Groups of Sprague-Dawley rats (5/sex/group) were given 0, 100,
200, 400 or 600 mg moxidectin/kg of diet, equal to 0, 12, 23, 26 or
31 mg/kg bw/day, for 28 days. Signs of toxicity were observed from day
1 of the study in animals given the three highest doses. These
included ataxia, tremors, salivation, piloerection and diuresis. At
the lowest level, hypersensitivity to touch was noted in males on day
2 (5/5) and 3 (1/5) of the study.
All the animals in the two highest dose groups died by day 8, and
2 female rats given 23 mg/kg bw/day died during the course of the
study. There were no mortalities in the lowest dose group. Food
intakes and body-weight gains were unaffected in the lowest dose group
but were significantly depressed in the three highest dose groups.
There were no effects on relative or absolute organ weights in
any group attributable to moxidectin intake. At the two highest dose
levels and in animals which died at the 23 mg/kg bw/day level, diffuse
atrophy of the liver, kidneys, heart, spleen, adrenals, thyroid,
testes, ovaries and epididymis occurred, which is typical of changes
often seen in anorexic animals. There were no abnormalities in animals
given the lowest dose level, nor in surviving rats given 23 mg/kg
bw/day moxidectin. A NOEL was not identified in this study because
hypersensitivity to touch was noted in several rats in the lowest
dose group at days 2 and 3 (Fischer, 1988).
Groups of Sprague-Dawley rats (10/sex/group) were given diets
containing 0, 25, 50, 100 or 150 mg moxidectin/kg of feed, equal to
0, 1.9, 3.9, 7.9 or 12 mg/kg bw/day, for 13 weeks. Signs of toxicity
in animals given the highest dose included hypersensitivity to touch,
lethargy, aggressive behaviour, tremors and urine-stained fur. At the
7.9 mg/kg bw/day level, hypersensitivity to touch began on day 5 but
cleared by day 14. No overt signs of toxicity were seen in rats given
the two lowest doses. At the highest dietary level, 3 females died or
were sacrificed in moribund condition.
Food intake was reduced in animals given the highest dietary
level of moxidectin for the first 2 weeks of the study. There was no
effect on food intakes in any of the other groups when compared with
control values. Body weights were depressed for the first 6 weeks in
rats given the highest dose level, and were decreased for the
remainder of the study. Body weights were also depressed in females
given 7.9 mg/kg bw/day.
Haematological values, clinical chemistry and urinalyses were
unaffected by moxidectin treatment.
Females given the highest dietary level had significantly
increased absolute kidney and adrenal weights, and increases in
relative kidney, liver, heart and adrenal weights. Significant
increases in absolute and relative adrenal weights in females, and
testes weights in males occurred at 7.9 mg/kg bw/day. These changes
are probably related to decreases in body weight. No changes in organ
weights occurred at the two lowest dietary intake levels.
No gross or microscopic abnormalities were observed in any of the
treatment groups. The NOEL in this study was 3.9 mg/kg bw/day
(Fischer, 1989b).
2.2.2.3 Dogs
Groups of pure-bred beagle dogs (2/sex/group) were given diets
containing 0, 20, 80 or 160 mg moxidectin/kg of feed, equivalent to
0, 0.5, 2 or 4 mg/kg bw/day, for 28 days. At the highest dose, dogs
developed anorexia, ataxia, prostration and diarrhoea. After day 5
they were returned to a control diet for 2 days and then resumed for
the remainder of the study on a diet containing 50 mg/kg of feed,
equivalent to 1.25 mg/kg bw/day.
Body weight and food consumption were depressed in dogs given the
two highest doses, but these increased or remained stable after week
1. In the two highest doses, tremors, a languid appearance, mydriasis,
ataxia, emesis, prostration, dehydration, sensitivity to touch, slight
salivation, no or few faeces and an inability to hold the head in the
normal position were observed, but these effects resolved in the
high-dose dogs after moxidectin intake was reduced. There were no
signs of toxicity seen in those given the lowest dose.
No haematological changes occurred and ophthalmoscopic
examinations gave normal results. There were no gross abnormalities at
necropsy but relative and absolute testes weights were reduced in dogs
given the two highest doses. Histopathological examination revealed
reductions in spermatogenetic activity in males given the two highest
doses. In animals given 2 mg/kg bw/day, there was a slight decrease in
colloid in the thyroid. The NOEL in this study was 0.5 mg/kg bw/day
(Schulze, 1989a).
In a 90-day study, groups of pure-bred beagle dogs (4/sex/group)
were fed diets containing 0, 10, 30 or 60 mg moxidectin/kg of feed,
equal to 0, 0.3, 0.9 or 1.6 mg/kg bw/day, for 90 days At the highest
dose, lacrimation, tremors, salivation, slight ataxia and a languid
appearance were noted. Dose-dependent reductions in absolute body
weights and food consumption were noted in dogs given the two highest
doses. No other signs were noted and there were no deaths during the
test period.
No abnormalities in haematological parameters, ophthalmoscopic
examinations or urinalyses were seen. Organ weights were comparable
with controls except in the high-dose females (decrease in absolute
heart weights) and high-dose males (slight decreases in absolute
pituitary and pituitary to brain weight ratios). No microscopic
abnormalities were seen. The NOEL in this study was 0.3 mg/kg bw/day
(Schulze, 1989b).
Groups of pure-bred beagle dogs (6/sex/dose) were given diets
containing 0, 10, 20 or 45 mg moxidectin/kg of feed, equivalent to
0, 0.26, 0.52 or 1.15 mg/kg bw/day, for 52 weeks. No signs of toxicity
occurred and body weights remained comparable to controls throughout
the study. There were no abnormalities in haematological parameters,
clinical chemistry or urinalyses, and ophthalmoscopic examinations
were normal. No gross or microscopic abnormalities were seen at
necropsy. The NOEL in this study was 1.15 mg/kg bw/day
(Schulze, 1991).
2.2.3 Long-term toxicity/carcinogenicity studies
2.2.3.1 Mice
Groups of CD-1 mice (65/sex/group) were given diets containing
0, 15, 30 or 60 mg moxidectin/kg of feed, equal to 0, 2.5, 5.1 or
12 mg/kg bw/day, for 2 years. After 9 weeks on the study, the highest
dose was reduced to 50 mg/kg of feed (7.9 mg/kg bw/day) because of
increased mortality in this group.
In the high-dose group, hunched-posture, decreased activity,
tremors, laboured breathing and coldness to the touch were observed.
During the last 13 weeks of the study, females in this group died or
were sacrificed in extremis and 10 surviving females in this group
were killed 2 days before scheduled sacrifice. No increase in
mortality was seen in males in this group. No other clinical signs
were evident in any of the other animals in all treated groups.
Body weights were slightly reduced in high-dose males during
weeks 0-8, probably because of reduced food intake. There were no
haematological abnormalities in treated animals at 12, 18 or 24 months
and no gross or microscopic changes were observed at termination.
There was no increased incidence of any tumour type. The NOEL in this
study was 5.1 mg/kg bw/day (Goldenthal, 1992).
2.2.3.2 Rats
Groups of Sprague-Dawley Crl:CD BR rats (65/sex/group) were given
diets containing 0, 15, 60 or 120 mg moxidectin/kg of feed, equal to
0, 0.8, 3.2 or 9.8 mg/kg bw/day, for 2 years. After 8 weeks on the
study, the highest dose was reduced to 100 mg/kg (5.1 mg/kg bw/day)
because of increased mortality in this group.
During weeks 1-8, 4 of the high-dose females were found dead or
were sacrificed in extremis. Signs of toxicity in this group included
hunched posture, tremors, hyperactivity, rough haircoat, urine-stained
fur, and hypersensitivity to external stimuli. These signs ceased when
the dose was reduced to 5.1 mg/kg bw/day. No signs of overt toxicity
were noted in the other treatment groups. Before the dose was reduced,
high-dose females had body weights significantly lower than controls
but these became similar to control values when the dose was reduced.
After the 2-year treatment period, there were no abnormalities in
haematological parameters, clinical chemistry or urinalyses. There
were no adverse findings on ophthalmoscopic examination of treated
rats. At termination, there were no gross or microscopic changes
observed and there was no increased incidence of any tumour type. The
NOEL in this study was 5.1 mg/kg bw/day (Zoetis, 1992).
2.2.4 Reproductive toxicity studies
2.2.4.1 Rats
In a pilot single-generation (two litters) study, groups of COBS
CD Sprague-Dawley derived rats (25/sex/group) were given diets
containing 0, 25, 50 or 125 mg moxidectin/kg of feed, equal to 1.8,
3.9 or 9.8 mg/kg bw/day for a 9-week period prior to mating and
through gestation and lactation to produce the F1a litters. The
dietary levels were reduced to 0, 5, 10 or 15 mg/kg, equal to 0, 0.4,
0.8 or 1.1 mg/kg bw/day, for the F1b litter.
At the highest dietary level, parental animals showed reductions
in weight gains, a decrease in the number of live pups at birth and an
increase in the number of dead pups at birth. All the live F1a pups
died on days 0-4 of lactation.
No adverse effects were seen in animals given the two lower dose
levels of moxidectin. Mating, fertility, gestation length and numbers
of pups born alive were comparable with controls. However, all the
F1a pups died during lactation.
No adverse effects were noted in parental animals following the
reductions in doses for the F1b litter. Gestation length and litter
size were also unaffected. At the mid-dose level, there was a
reduction in pup survival rate at days 4-21, while in the high-dose
group, mean pup weights were reduced at days 4, 7, 14 and 21 of
lactation and pup survival at days 0-14 and 4-21 of lactation was
lower than in controls. There were no effects on pups in the lowest
dose group.
Gross examination of the parental animals and of the F1b pups
from treated rats showed no adverse effects. The NOEL in this study
was 0.4 mg/kg bw/day for the F1b animals (Schroeder, 1991).
In a 3-generation (2 litters) study in COBS CD Sprague-Dawley-
derived rats, groups of 25 males and 25 females were given diets
containing 0, 1, 2, 5 or 10 mg moxidectin/kg of feed, equal to 0,
0.07, 0.15, 0.41 or 0.83 mg/kg bw/day for a 70-day period prior to
mating. Randomly selected offspring (F1b and F2b) were
selected to produce the ensuing generations, while randomly selected
offspring of the F1b, F2b and F3b generations were sacrificed
and examined for gross abnormalities. Selected tissues from these
animals (reproductive organs, pituitary and gross lesions from
parental animals) were subject to microscopic examination.
No excess mortality was seen in any of the parental generations
(P1, F1 or F2). No adverse effects were seen in the 0.07, 0.15
or 0.41 mg/kg bw/day treatment groups with respect to growth, food
consumption, maternal weight changes during gestation and lactation,
reproductive performance or fertility indices. Pup weights, sex
distribution and pup survival were comparable with controls.
At the highest dietary level, slight reductions in weight were
seen in males during the pre-mating (F2), mating and post-mating
periods (F1 and F2). Significant reductions in pup survival
indices were noted for days 0-21 for the F1a litters, and for days
0-4 for the F2a litters. Other parental and neonatal parameters were
unaffected by compound administration.
Gross examination of the P1, F1 and F2 parental animals and
of selected F1b, F2b and F3b animals showed no compound-related
effects while microscopic examination of primary and secondary sex
organs revealed no abnormalities. The NOEL in this study was 0.4 mg/kg
bw/day (Schroeder, 1992).
2.2.4.2 Dogs
As part of a target species safety study, adult male beagle dogs
were given oral doses of 9 µg moxidectin/kg bw, once every 30 days for
4 consecutive months. Semen quality, breeding ability and performance
were unaffected and there were no gross or microscopic adverse effects
seen at necropsy (Rooney, 1993a).
2.2.4.3 Cattle
There were no effects on ovulation, folliculogenesis, post-
ovulation or pregnancy in estrous cycling cows when animals were
given 0.6 mg moxidectin/kg bw by s.c. injection (Wang, 1991c).
No effects were noted in bulls given 3-fold the therapeutic dose
(0.6 mg/kg bw) of moxidectin by s.c. injection; semen quality was
normal as was palpation of the seminal vesicles and testes. The
circumference of the scrotum was normal (Wang, 1992).
2.2.5 Special studies on embryotoxicity and/or teratogenicity
2.2.5.1 Rats
Groups of 25 pregnant Crl:CD Sprague-Dawley BR rats were given
gavage doses of 0, 2.5, 5, 10 or 12 mg/kg bw/day moxidectin in corn
oil from days 6-16 of gestation, when the animals were killed by
carbon dioxide asphyxiation. No deaths occurred in this study, but the
12 mg/kg bw/day dose resulted in urine-stained fur, and chromo-
dacryorrhea. The 10 and 12 mg/kg bw/day doses resulted in
significant decreases in maternal body weights and decreases in food
consumption. In the post-dosing period (16 to 20 days of gestation),
significant increases in food consumption and body weights occurred in
these animals. However, the body weights were still reduced compared
with controls, even after a correction for gravid uterine weights was
made.
Administration of 10 and 12 mg/kg bw/day resulted in significant
increases in the total number of fetuses with abnormalities, typified
by increased incidences of cleft palate and wavy or incompletely
ossified ribs. No other effects were seen and it is likely that these
abnormalities were due to embryotoxic effects or maternal toxicity.
There was no evidence of teratogenic effects and the NOEL in this
study was 5 mg/kg bw/day (Lochry, 1989).
2.2.5.2 Rabbits
Groups of 18 pregnant Hra:(NZ)SPF rabbits were given gavage doses
of 0, 1, 5 or 10 mg/kg bw/day moxidectin in corn oil from days 7-19 of
gestation, when the animals were sacrificed. No deaths occurred in
this study, but 1 control and 1 high-dose rabbit died as a result of
gavage accidents. Two low-dose animals and 1 high-dose animal aborted
during the course of the study, which was not considered to be
compound-related and the incidence was within the range for historical
controls.
Dose-related decreases in body weights occurred at 5 and
10 mg/kg bw/day, accompanied by decreases in feed intake, but
pregnancy rates in all treated groups were similar to control values.
There were no effects on numbers of corpora lutea, implantations or
resorptions when compared to control values, and fetal body weights
and sex ratios were similar in all groups.
There was no increased incidence of external, soft tissue or
skeletal abnormalities in any dosed group when compared with controls.
On the basis of maternal effects demonstrated by depression in
body-weight gains, the NOEL in this study was 1 mg/kg bw/day. There
was no evidence of teratogenicity up to the highest dose employed in
this study (Hoberman, 1989).
2.2.5.3 Dogs
As part of a target animal safety study, a group of 24 pregnant
beagle dogs was given orally 9 µg/kg bw moxidectin (3-fold the
therapeutic dose) from day 12 of gestation until day 42 of lactation.
There were no effects on the outcome of pregnancy and no abnormalities
were seen in pups from treated dogs (Rooney, 1993b).
2.2.5.4 Cattle
No adverse effects were seen in cattle when moxidectin, as a
single s.c. injection, was given in the first, second or third
trimester of pregnancy to a total of 135 animals, using a dose of
0.6 mg/kg bw (3-fold the recommended therapeutic dose) (Wang, 1991a).
No adverse effects were noted in another study where 15 pregnant
cows were given a single s.c. injection of 0.2 mg/kg bw during the
first, second or third trimester of pregnancy (Wang 1991b).
2.2.5.5 Sheep
The outcome of pregnancy was unaffected when a group of 20
animals was given a single s.c. injection of 0.4 mg/kg bw moxidectin
(2-fold the therapeutic dose) at unspecified periods of pregnancy
(Parker, 1994). Similar findings were made in other studies
(Cobb, 1994).
2.2.5.6 Horses
Breeding and pregnant mares received oral doses of 1.2 mg/kg bw
moxidectin (3-fold the therapeutic dose) every 2 weeks during
gestation, or for various periods post-foaling. Moxidectin treatment
did not affect the outcome of pregnancy (American cyanamid, 1993).
2.2.6 Special studies on genotoxicity
The results of genotoxicity studies with moxidectin are
summarized in Table 2. Moxidectin was not mutagenic in the Ames test,
in a forward mutation assay with E. coli, or in a test using mammalian
cells in vitro. A negative result was obtained in an in vivo study
for chromosome aberrations in rat bone marrow cells. It did not induce
UDS in primary rat hepatocytes.
2.2.7 Special studies on skin irritation
Only mild signs of skin irritation were seen in New Zealand white
rabbits exposed to moxidectin for periods of up to 72 h (Fischer,
1990 g,h).
2.2.8 Special studies on eye irritation
Moderate signs of eye irritation were noted when moxidectin
(0.1 g) was instilled into the conjunctival sac of New Zealand white
rabbits. The irritation resolved 48-72 h after treatment
(Fischer, 1990i).
2.2.9 Special studies on dermal sensitization
No evidence of skin sensitization was seen when male Hartley
guinea-pigs were exposed to moxidectin using the Buehler method. The
positive control, 1-chloro-2,4-dinitrobenzene gave the expected
positive response (Ventura, 1990).
2.2.10 Special studies on pharmacodynamic effects
In a radioligand binding study, moxidectin stimulated the
t-butyl-bicyclophosphorothionate binding to rat cortical membranes in
a similar manner to ivermectin. In another study, the drug stimulated
the binding of flunitrazepam to rat brain membranes. Such studies
suggest that moxidectin has activity at the GABA-A receptor in a
manner similar to ivermectin, and this may contribute to its mode of
action against parasites. However, it is known that ivermectin has
more than one mechanism of action and this is also likely to be true
of moxidectin (Ingle & Wood, 1990).
Moxidectin was investigated in a variety of screening tests for
pharmacodynamic action. It had no CNS effects, nor any effects on
motor activity, blood pressure, heart rate or respiration rate, and
did not cause haemolysis of sheep red blood cells. It did induce weak
contractions or relaxation of tracheal smooth muscle but these were
not antihistamine or anticholine smooth muscle induced effects. It
also increased GI motility in guinea-pig isolated ileum (Ingle, 1990).
Table 2. Results of genotoxicity studies on moxidectin
Test system Test object Concentration Results Reference
Ames test1 S. typhimurium
TA98, TA100, 50-300 µg/ neg. Traul 1990a
TA1535, TA1537, plate
TA1538
Reverse
mutation E. coli 50-2000 µg/ neg. Traul 1990a
assay1 WP2 uvrA- plate
Forward
mutation CHO (HGPRT locus) 0.01-15 µg/ml neg. Traul 1990b
assay1
In vivo
cytogenetics Rat bone marrow 0-150 mg/kg neg. Sharma 1990
assay bw
UDS Primary rat 0.1-30 µg/ml neg. Curren 1990
hepatocytes
1 Both with and without rat liver S9 fraction.
3. COMMENTS
The Committee considered data from pharmacodynamic,
pharmacokinetic, metabolism, acute and short-term toxicity,
carcinogenicity, genotoxicity, reproductive toxicity and
teratogenicity studies.
The pharmacokinetics and metabolism of moxidectin were studied in
rats, sheep and cattle. After oral administration to sheep, about 20%
of the dose was absorbed. The drug, which is very lipophilic, was
found at high levels in fat, but at much lower levels in other
tissues. It was excreted in the milk. After oral administration to
rats, the major compound recovered in faeces was the parent drug,
while small amounts of hydroxylated metabolites were found in liver
and faeces. Hydroxylated metabolites were observed in sheep and cattle
given oral doses of the drug.
Orally administered moxidectin was found to be moderately toxic
with LD50 values of the order of 50-100 mg/kg bw.
In a 28-day oral toxicity study in mice in which moxidectin was
administered in the feed, signs of toxicity included tremors and
hypersensitivity to touch. All mice given the highest dose of 32 mg/kg
bw/day died. The NOEL in this study was 6.9 mg/kg bw/day.
Rats given up to 31 mg moxidectin/kg bw/day in a 28-day feeding
study developed ataxia, tremors, salivation, piloerection and
diuresis. At 23 mg/kg bw/day and above, dose-related diffuse atrophy
of the liver, kidneys, heart, spleen, adrenals, testes, epididymis and
ovaries was seen. A NOEL was not identified in this study because
hypersensitivity to touch was noted in the lowest-dose group (12 mg/kg
bw/day) at days 2 and 3. Similar findings were noted in a 13-week
feeding study in rats, in which the NOEL was 3.9 mg/kg bw/day.
In a 28-day toxicity study in dogs given up to 4 mg of
moxidectin/kg bw/day in the feed, animals given the highest dose
developed anorexia, ataxia, prostration and diarrhoea until the dose
was reduced to 1.25 mg/kg bw/day. The NOEL was 0.5 mg/kg bw/day. In a
90-day feeding study in dogs, lacrimation, tremors, salivation and
slight ataxia were noted in animals given the highest dose of
1.6 mg/kg bw/day. No major histopathological changes were observed in
this study. The NOEL was 0.3 mg/kg bw/day. No signs of toxicity were
noted in a 52-week feeding study in dogs. The NOEL was 1.15 mg/kg
bw/day, the highest dose used.
A pilot single-generation reproductive toxicity study was
performed in rats, in which moxidectin was administered at doses of up
to approximately 10 mg/kg bw/day for a 9-week period before mating and
during gestation and lactation. None of the offspring of animals in
the highest-dose group survived. Survival rates were decreased in the
progeny of animals given lower doses, but there were no findings which
could be attributed to effects on fertility. The NOEL in this study
was 0.4 mg/kg bw/day. In a three-generation reproductive toxicity
study in rats given doses of up to 0.83 mg/kg bw/day for a 70-day
period before mating, there were no effects on mortality or on
fertility except at the highest dose, where slight reductions in male
body weights and significant reductions in pup survival were seen. The
NOEL was 0.4 mg/kg bw/day.
In a teratogenicity study in rats dosed at 10 or 12 mg
moxidectin/kg bw/day, there was evidence of both materno- and
fetotoxicity, as shown by increased incidences of cleft palate and
wavy or incompletely ossified ribs. There was no evidence of
teratogenic effects, and the NOEL in this study was 5 mg/kg bw/day. In
a teratogenicity study in rabbits, there was evidence of materno-
toxicity at 5 and 10 mg/kg bw/day, but no evidence of fetotoxicity
or teratogenicity. The NOEL in this study, based on maternal effects,
was 1 mg/kg bw/day.
In a long-term toxicity/carcinogenicity study in CD-1 mice,
moxidectin was administered in the diet at concentrations equal to
0, 2.5, 5.1 or 12 mg/kg bw/day for 2 years. After 9 weeks, the highest
dose was reduced to 7.9 mg/kg bw/day because of toxic effects that
included deaths, hunched posture, decreased activity, tremors and
laboured breathing. There were no effects on haematological parameters
and no increases in the incidence of any types of tumour were
observed. The NOEL was 5.1 mg/kg bw/day.
A 2-year toxicity/carcinogenicity study was conducted in
Sprague-Dawley rats which were given moxidectin in the diet at
concentrations equal to 0, 0.8, 3.2 or 9.8 mg/kg bw/day. After 8
weeks, the highest dose was reduced to 5.1 mg/kg bw/day because of
signs of toxicity that included hunched posture, tremors,
hyperactivity, urine-stained fur and hypersensitivity to external
stimuli. At the end of the 2-year period there was no evidence of
toxicity and no increased incidence of any type of tumour. The NOEL
was 5.1 mg/kg bw/day. The Committee concluded that moxidectin has no
carcinogenic potential.
Moxidectin has been tested in bacterial mutation assays, in a
forward mutation assay in Chinese hamster ovary cells, in a test for
UDS in primary rat hepatocytes, and in an in vivo cytogenetic assay
in rat bone marrow. All gave negative results, and the Committee
concluded that moxidectin had no genotoxic potential.
4. EVALUATION
The Committee concluded that the most relevant effects for the
toxicological evaluation of moxidectin were those observed in the
90-day study in dogs, where the NOEL was 0.3 mg/kg bw/day. Based on
this NOEL and using a safety factor of 200 to account for the
uncertain sensitivity of the test system used to assess the
neurotoxicity of moxidectin (Annex 1, reference 119, section 2.2), the
Committee established an ADI of 0-2 µg/kg bw for moxidectin. The ADI
was rounded to one significant figure, consistent with accepted
rounding procedures (Annex 1, reference 91, section 2.7). This ADI
provides an adequate margin of safety for the effects noted in the
reproductive toxicity studies in rats.
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