PACLOBUTRAZOL
EXPLANATION
Paclobutrazol is a plant growth regulator. It was reviewed for
the first time at the present meeting.
EVALUATION FOR ACCEPTABLE INTAKE
BIOLOGICAL DATA
Biochemical aspects
Absorption, distribution and excretion
Rats
A single dose of 5 mg(2MBq)/kg 14C-paclobutrazol (triazole-
labelled) was administered orally to four male and four female
Crl:CD(SD)Br rats. By seven days post-dosing, 96-97% of the
administered dose had been recovered in both sexes, with 58-65% in
urine and 28-37% in faeces. In urine, 70-75% of the total urinary
radioactivity was recovered in the first 24 hours, and 95-96% in the
first 72 hours. Recovery of radioactivity by the faecal route was
57-74% in the first 48 hours and 96-98% by 120 hours. Measurable
radioactivity was found in the GI contents and liver of most of the
animals and in the carcass of one male and the kidney of one female
(Cresswell et al., 1983).
In a similar study a single oral dose of 14C-paclobutrazol
(triazole-labelled) at 250 mg(2MBq)/kg bw was given to four male and
four female CRI:CD(SD)Br rats. Approximately 98% of the administered
radioactivity was recovered in urine, faeces and cage washings in both
sexes during the 168 hours following dosing: 51-54% in urine, 43-45%
in faeces. Approximately 75% of urinary radioactivity was collected in
the first 48 hours and about 70-88% of faecal radioactivity was
collected by 72 hours (mainly 24-72 hours). Radioactivity was detected
in GI contents and liver of most of the animals and in the carcass of
one female (Cresswell et al., 1984a).
A single dose of 10 mg of triazole-labelled 14C-paclobutrazol
(1.93 MBq/mg)/kg bw was administered by gavage to three male and three
female Alderlay Park rats. A total of 32-48% of the administered
radioactivity given to the males was recovered in urine over four days
and 44-61% in faeces, with 89% of the urinary radioactivity collected
in the first 24 hours and 92% of faecal radioactivity in the first
48 hours. In females 48-56% of the radioactivity was recovered in
urine and 34-41% in faeces with 84% of urinary radioactivity collected
in the first 24 hours and 82% of faecal radioactivity in the first 48
hours. Tissue residues were low at 96 hours. The highest residues were
in liver: 0.08 µg equiv./g tissue in males and 0.18 µg equiv./g tissue
in females. Detectable amounts of radioactivity were observed in
kidney, testes/ovary and fat (Jones et al., 1983).
As part of the same study one additional male and one additional
female Alderlay Park rats were given 10 mg (10.6 MBq/mg)
14C-(triazole-labelled)paclobutrazol/kg bw by savage. At 72 hours
post-dosing the animals were sacrificed, frozen, and sectioned for
autoradiogram preparation. The majority of the radioactivity was found
in the GI tract with small intestine > large intestine > stomach.
The only organ showing labelling was the liver, which was lightly and
uniformly labelled (Jones et al., 1983).
A second autoradiography study in the rat was performed with
14C-triazole-labelled paclobutrazol at a dose level of 250 mg/kg bw
given to one male and one female Alpk/AP rat by gavage. A total of 60%
of the administered dose in the male and 45% in the female was
recovered during the 48 hours before sacrifice. Very little
radioactivity was recovered in expired CO2 in either sex.
Proportions of urinary and faecal excretion were similar in the male
(about 29% recovered via each route), but urinary excretion
predominated in the female (36% vs. 7% by the faecal route). The
autoradiograph indicated that the majority of labelling was in the GI
tract with similar amounts in small and large intestine and less in
stomach in the male and similar amounts in stomach and small intestine
and less in large intestine in the female. Lower amounts of
radioactivity were observed in the liver and kidney. Liver was
uniformly labelled. The renal pelvis contained more radioactivity than
the cortex or medulla. A few foci of radioactivity were seen in
perirenal fat in both sexes (Jones et al., 1984).
A single oral dose of 250 mg/kg bw 14C-paclobutrazol
(triazole-labelled) was administered to 10 female Alpk/AP rats.
Urinary excretion accounted for 38-70% of the administered
radioactivity with 85% of this amount recovered in the first 48 hours
(primarily between 24 and 48 hours). Faecal excretion accounted for
14-45% of the administered dose. Of this, 93% was recovered between 24
and 72 hours.
Administration of 14C-paclobutrazol as a single oral dose of
250 mg/kg bw to two male and two female bile cannulated rats resulted
in the recovery of radioactivity in bile of 75% of the dose in males
and 55% in females. Faecal excretion accounted for 3% of the dose in
males and 7% in females, while urinary excretion accounted for 20% in
males and 33% in females. The biliary route is, therefore, of
considerable importance in the elimination of paclobutrazol in the rat
(Jones et al., 1986).
Groups of 3 male rats received daily oral doses of 5 mg
14C-paclobutrazol (triazole-labelled)/kg bw/day for 3, 7, 14, 21,
28, 35, 42 days (1 group each), or 49 days (7 groups). The rats were
sacrificed one day after the final dose, except for the six extra
groups dosed for 49 days, which were sacrificed 3, 7, 14, 21, 28 and
35 days after the final dose, respectively. Twenty-four-hour recovery
of radioactivity after one dose was 70%, with 41% in urine and 29% in
faeces. After 49 doses, 24-hour recovery was 58%, with 44% in urine
and 14% in faeces. Tissue levels of radioactivity increased with
increasing duration of dosing. Highest concentrations were observed in
liver at all intervals, followed by kidney and blood. Fat levels were
low or undetectable.
Tissue levels declined to undetectable levels in fat and blood by
21 days and in kidney and liver by 28 days. The reduction in
radioactivity from day 42 levels appeared to be biexponential in liver
and kidney. The half-lives of each phase of the decline were 1.36 and
6.69 days for liver and 1.56 and 9.26 days for kidney. Blood levels
declined rapidly with a half-life of 3.16 days (Greenslade et al.,
1984).
Dogs
14C-paclobutrazol (triazole-labelled) was administered as a
single oral dose of 5 mg (0.2 HBq)/kg bw to three male and three
female beagle dogs. Peak blood and plasma levels were observed 0.5-1.5
hours after dosing. Peak mean plasma levels were 4.453 and 4.105 µg
equiv./ml in males and females, respectively. Peak mean blood levels
were 2.821 and 2.650 µg equiv./ml, respectively. Blood and plasma
levels declined rapidly to four hours and then more slowly. Blood
levels were below the limit of detection by 48 hours in both sexes.
Plasma levels were not detectable by 72 hours in males and 48 hours in
females. Half-life in plasma was 8.1 hours in males and 7.7 hours in
females; in blood: 5.3 hours in males and 7.5 hours in females.
A total of 93% in males and 97% in females of the administered
radioactivity was recovered in urine, faeces and cage washings in 168
hours with excretion by the urinary route somewhat higher: 51-57% in
urine and 33-42% in faeces. Excretion was relatively rapid: 93-95% of
urinary radioactivity and 76-80% of faecal radioactivity was collected
in the first 24 hours after dosing.
Tissue levels were below the limit of detection except in one
male, where 0.057 µg equiv./g tissue was detected in the liver
(Cresswell et al., 1984b).
Biotransformation
The metabolism of paclobutrazol was studied in the rat. Metabolic
profiles in urine, bile and faeces from Alpk/AP rats given either 5 or
250 mg 14C-paclobutrazol (triazole-labelled)/kg bw indicated
extensive metabolism. However, biotransformation was limited to the
tertiary butyl moiety with no metabolism detected in the triazole or
halogenated phenyl rings. The two main metabolites in urine, bile and
faeces were paclobutrazol diol and paclobutrazol acid, which were both
excreted in conjugated and unconjugated forms. A mechanism of
biotransformation involving a two-stage oxidation process by way of
the hepatic mixed function oxidase system is proposed.
Following oxidation to the diol the fate of the compound
(excretion or further oxidation to the carboxylic acid) was sex- and
dose-dependent. At 250 mg/kg bw males excreted about 20% of the dose
in urine (mainly as the acid) while females excreted about 30% of the
dose by this route, but mainly as free and conjugated diol (2/3 diol,
1/3 acid). At 5 mg/kg bw the same pattern was observed in males but
females excreted a higher percentage of acid than at 250 mg/kg. In
both sexes most of the dose was excreted in bile in the form of diol
conjugates which were eliminated in faeces. The authors conclude that
the males had a greater capacity to oxidize paclobutrazol than the
females (Jones et al., 1986).
Toxicological studies
Special studies on oncogenicity
Mice
Groups of 51 weanling Charles River Crl:CD-1(ICR)BR(SPF)
mice/sex/dose were given diets containing 0, 25, 125 or 750 ppm
paclobutrazol (92.4% pure) for 104 weeks. Additional groups of 12
mice/sex/dose were given the same diets for 52 weeks for interim
examination. Dietary analyses prior to feeding indicated that the
diets were generally in the range of 90-100% of the nominal
concentration. There were no treatment related clinical signs of
toxicity. Mortality was not dose-related. At 76 weeks 75-90% of the
males and 86-96% of the females were alive. No effects were observed
on body weights or water intake. Food consumption was slightly higher
in the 750 ppm group during the first few weeks of the study but the
observation was not considered to be biologically significant. There
were no toxicologically significant changes in haematological or
clinical chemistry parameters at either 52 or 104 weeks with the
possible exception of reduced triglyceride values in males in the
750 ppm group at both intervals.
Liver weights were significantly increased at week 52 in males
given 750 ppm diet and at week 104 in males and females in this dose
group. At termination, males at the 750 ppm dose level had increased
severity of the liver steatosis which was observed in virtually all of
the males. A similar increase in severity was not observed in females.
No other lesions appeared to be treatment-related. A number of tumour
types were observed in all groups. No treatment-relationship was
indicated by the incidence of any individual rumour type or by the
overall incidence of tumours. The NOEL in this study was 125 ppm
(equal to 15 mg/kg bw/day based on food intake and body weight)
(Shaw, 1986a).
Rats
Groups of 50 weanling outbred Crl:CD(SD)BR (Sprague-Dawley
derived) rats/sex/dose were given diet containing 0, 50, 250 or
1250 ppm paclobutrazol (92.4% pure) for 104 weeks. Additional groups
of 10 rats/sex/dose were given the same diets for 52 weeks for interim
examination. Diet analyses indicated that the concentrations were
generally 90-100% of the nominal concentration. No effects were noted
on the clinical condition of the animals or their survival. At 104
weeks 58-66% of the males and 42-56% of the females were alive.
Survival did not drop below 50% until after week 100. Cumulative
body weight gains in females were consistently and significantly lower
than controls in the 1250 ppm group but males were not affected.
During the early weeks of the study food and water consumption in the
1250 ppm females was slightly lower than in controls. Platelet counts
were lower in the 1250 ppm group throughout the study in males and
during the second year in females. Considerable variability was
observed in clinical chemistry values and differences noted could not
be unequivocably related to treatment. Urine parameters were not
affected. Liver weights were increased in both males and females in
the 1250 ppm group at termination but not at week 52. The only
non-neoplastic histopathological lesion which was treatment related
was an increased incidence of large hepatocytes which was frequently
accompanied by steatosis. This lesion was primarily observed in males
and females at 1250 ppm but was also observed in eight males at
250 ppm and one control male.
A number of tumour types were observed but the incidence of
individual tumour types was generally similar in all groups. The
number of males with malignant tumours was slightly higher in treated
groups than controls, especially in the 1250 ppm group. In this group
the increase was primarily due to the occurrence of gliomas (3 vs. 9
in controls) and haemolymphoreticular neoplasias of various types
(5 vs. 1 in controls). In females gliomas were observed only in the
250 ppm group, suggesting that the glioma incidences are cluster
observations unrelated to treatment. The NOEL in this study was
250 ppm (equal to 11 mg/kg bw/day based on food intake and body
weight) (Shaw, 1986b).
Special studies on mutagenicity
Paclobutrazol was negative in four of six mutagenicity studies.
In the two studies (micronucleus assay in mice and cytogenetic assay
in rats) in which equivocally positive results were observed, the
assay was in bone marrow and the positive results were observed at the
first sampling time in both sexes. Variability observed in the
negative controls in both studies suggest that these studies should be
repeated to clarify results (Table 1).
Special study on reproduction
Groups of 30 female and 15 male weanling Alpk/AP (Wistar-derived)
rats were given diet containing 0, 50, 250 or 1250 ppm of
paclobutrazol (92.4% pure). After 11-12 weeks the animals were mated
on a 2:1 basis. If mating did not occur within ten days the male was
replaced by a proven male. The F0 parents were mated twice (F1a
and F1b) and the F1 parents only once (F2a). Diets were maintained
throughout all phases of the study.
In the parental generations, both males and females given
1250 ppm had lower body weight gains than controls but food intakes
were lower only in females. In the F0 parents there was a low
incidence in all groups of thickened eyelids, chromodacryorrhea and
twisted snout/dental malocclusion. In the F1 parents these
observations were largely confined to the 250 and 1250 ppm groups but
were considered elevated only in the 1250 ppm females, Mating
performance, pregnancy rate, duration of gestation, litter size and
litter viability were unaffected by treatment. Pup weight gains were
reduced only at 1250 ppm in F2a pups just prior to weaning. The pups
showed the same clinical signs as the parents with variable incidences
of chromodacryorrhea, thickened eyelids and malocclusion/twisted
snout, which appeared to be elevated only at 1250 ppm. Liver weights
were increased in the parental females and in both male and female
pups of all litter generations in the 1250 ppm group only.
Centrilobular fatty changes in liver were observed in the F0 parent
females and the Fla and F2a pups of both sexes at 1250 ppm. There were
no histopathological changes related to the clinical observations. The
NOAEL for toxic effects in this study was considered to be 250 ppm
(equivalent to 12.5 mg/kg bw/day) and the NOEL for reproductive
effects was 1250 ppm paclobutrazol (equivalent to 62.5 mg/kg bw/day)
(Wickramaratne, 1987).
Special studies on teratogenicity
Rats
Groups of 24 mated female Alpk/AP, SPR (Wistar-derived) rats were
administered paclobutrazol (92.4% pure) at dose levels of 0, 40, 100
or 250 mg/kg by/day by gavage on days 615 of gestation. The day a
positive vaginal smear was obtained was designated gestation day 0.
Table 1. Results of mutagenicity on paclobutrazol
Concentration of
Test system Test organism paclobutrazol Results Reference
Ames test 1/ Salmonella 1.6-5000 µg/plate negative Callander,
typhimurium 1982
TA98, TA100,
TA1535, TA1537
and TA1538
Mouse lymphoma Mouse L5178Y 1.0-100 µg/ml negative McGregor &
assay 1/ TK +/- cells Riach, 1983
Micronucleus Mouse 0-140 mg/kg equivocally Phillips
assay (bone in corn oil weakly et al., 1983
marrow clastogenic 2/
Gytogenetic Rat 0-300 mg/kg equivocally Richardson
assay (bone in corn oil weakly et al., 1984
marrow) clastogenic 2/
Unscheduled DNA Rat 0-400 mg/kg bw negative Trueman, 1986
synthesis (liver) in corn oil
Dominant lethal Mouse 0-300 mg/kg bw negative Wickramaratne
test by gavage for et al., 1983
5 days
1/ With and without metabolic activation
2/ Reviewer's conclusion. Authors concluded negative results, noting high variability in negative
controls in both studies. The studies should have been repeated.
In the 250 mg/kg bw/day group one female died and four were
killed in moribund condition after 2-5 doses. There were no deaths in
the other groups. Signs of urinary incontinence were noted at a higher
frequency in the 250 mg/kg bw/day group. At 250 mg/kg bw/day body
weight gain, food consumption and food utilization were reduced during
the dosing period days 6-9. Body weight gain was also reduced at
100 mg/kg bw. There were no treatment-related effects on numbers of
implantations, live foetuses, early or late deaths, or on the sex and
weight of the foetuses. Cleft palate was observed in one foetus (of
297 examined) at 40 mg/kg bw/day and three foetuses (of 234 examined)
at 250 mg/kg bw/day. It is stated that in a preliminary study six
foetuses (of 85 examined) at 240 mg/kg bw had cleft palate. These
foetuses were all in one litter. There were single foetuses with cleft
palate at 0 and 80 mg/kg bw in this preliminary study. There was a
dose-related increase in skeletal abnormalities with impaired
ossification at all dose levels. These observations were suggestive of
a foetotoxic effect and a no-effect level could not be established
(Killick et al., 1983a).
Groups of 24 mated female Alpk/AP (Wigtar-derived) SPF rats were
administered paclobutrazol (92.4% pure) by gavage at dose levels of 0,
2.5, 10, 40 or 100 mg/kg bw/day on days 7-16 of gestation. In this
study the day a positive vaginal smear was obtained was designated
gestation day 1.
There were no deaths and no clinical signs of toxicity. No
treatment-related effects were noted on maternal body weight, food
consumption, numbers of implantations, early deaths, late deaths, or
live foetuses, sex and weight of foetuses, or uterine weights. The
only major external/visceral defect which appeared treatment-related
was unilateral hydroureter in eight foetuses (from 4 litters) at
100 mg/kg bw/day. No foetus had cleft palate. There was a significant
increase in the incidence of kidney and ureter defects at 40 and
100 mg/kg bw/day. There was a dose-related increase in severity of
these lesions as well. Considered with these changes the incidence of
hydroureter at 100 mg/kg appeared to be a foetotoxic effect rather
than a teratogenic effect. There were also increased incidences of
extra (14) ribs and impaired skeletal ossification at 40 and
100 mg/kg bw/day. The NOEL for foetotoxic effects in this study was
10 mg/kg bw/day. Considering the incidence of cleft palate in the
previous study (although it was not observed in this study), it seems
reasonable to consider 100 mg/kg bw/day as the NOEL for teratogenic
effects (Killick et al., 1984).
Rabbits
Female New Zealand White rabbits were mated with proven males
from the same supplier. Due to poor mating performance, however,
artificial insemination was used to supplement the natural matings.
Groups of 18 mated (or inseminated) females were administered
paclobutrazol (92.4% pure) at doses of 0, 25, 75 or 125 mg/kg bw/day
by gavage on days 6-18 of gestation (day of mating designated day 0 of
gestation).
Two deaths occurred in each of the control and 125 mg/kg bw/day
groups. Two females at 75 mg/kg bw/day aborted and were sacrificed.
The females in the 125 mg/kg bw/day group lost weight on days 6-9 of
gestation but thereafter showed similar body weight gains as observed
in the other groups. Food consumption was variable and not clearly
influenced by treatment. Pregnancy rate was low in this study: 56, 67,
83 and 50% at 0, 25, 75 and 125 mg/kg bw/day, respectively. Overall
pregnancy was higher in females mated naturally (84%) than in those
inseminated artificially (43%). There were no treatment-related
differences between groups in numbers of corpora lutea, implantations,
early or late intra-uterine deaths, live foetuses, or dams with
intra-uterine deaths. Sex ratio of foetuses, uterus weight, total
litter weight and mean litter weight were not affected by treatment.
Major defects were observed only in the treated groups (Table 2A)
but, with the exception of the multiple vertebral defects, were
consistent with the expected rates of spontaneous defects observed in
historical controls in this laboratory. There was no indication of a
treatment relationship for minor defects, skeletal variants or fore or
hind limb ossification scores (Killick et al., 1983b).
Because of the poor mating performance and often unsuccessful
artificial insemination, the numbers of pregnant females in the
control and 125 mg/kg bw/day were less than that normally considered
to acceptable for an adequate study. The authors, therefore, did not
consider the study to be fully adequate and a second study was
undertaken.
In the second study all females were artificially inseminated.
Groups of 18 females were given paclobutrazol (92.4% pure) at dose
levels of 0, 25, 75 or 125 mg/kg bw/day by gavage on days 7-19 of
gestation. The day of insemination was designated day 1 of gestation.
No treatment-related effects were observed on clinical condition.
During the first days of dosing (days 7-10), the 125 mg/kg bw/day
group lost weight but there were no effects after this period. Food
intake was slightly lower in this group. In this study pregnancy rates
were higher with 83-94% of the females in each group pregnant. Numbers
of corpora lutea and implantation sites were similar in all groups.
Post-implantation loss was slightly increased in the 125 mg/kg bw/day
group as a result of a higher incidence of late intra-uterine deaths.
However, the incidence of early intra-uterine deaths were lower than
controls in this group and the number of live foetuses did not suggest
a treatment-related effect. Sex ratio was similar in all groups. No
effect was observed on uterus weights. However, mean foetal weight was
slightly lower in the 125 mg/kg bw/day group and mean litter weights
slightly lower in both the 75 and 125 mg/kg bw/day groups.
Major defects were observed in 2/109, 4/129, 3/103 and 5/106
foetuses at 0, 25, 75 and 125 mg/kg bw/day, respectively. The types of
defects (Table 2B) were similar to those observed in the previous
study except that the only vertebral column defect was scoliosis. The
multiple vertebral defects observed previously were not seen in this
study. The incidence of severe flexure of forepaws was increased in
the 125 mg/kg bw/day group compared to current and historical
controls.
A few minor defects and variations occurred at slightly increased
incidences in the 125 mg/kg bw/day group. These were pale spleen,
partial ossification of the transverse process of the cervical
vertebra and the presence of 13 ribs (normal length or short
floating). At 75 mg/kg bw/day, only the incidence of partial
ossification of the transverse process of the 7th cervical vertebra
was slightly increased compared to controls. This observation did not
appear to be clearly indicative of an embryotoxic effect at this dose
level (Killick et al., 1986).
Overall, the dose level of 75 mg/kg bw/day appeared to be a NOEL
for embryotoxic effects. It may be that the NOEL for teratogenic
effects is 125 mg/kg bw/day but although the incidence of
malformations at this dose level in the two studies was not
consistent, a teratogenic effect cannot be ruled out at this time.
Therefore, it seems reasonable to accept 75 mg/kg bw/day as a
conservative NOEL for teratogenic effects.
Acute toxicity
The acute toxicity of paclobutrazol to several animal species is
given in Table 3. Signs of toxicity following oral or i.p.
administration were subdued behaviour, unsteady gait, signs of urinary
incontinence in rats and mice, and hypothermia. Signs of toxicity
following dermal administration of a dose of 2000 mg/kg bw were
urinary incontinence, upward curvature of the spine and desquamation
of the application site. No effects were observed after dermal
application of 1000 mg/kg bw.
Table 2A. Malformations in rabbits in teratology study with paclobutrazol
Number of foetuses (litters)* affected
mg/kg/day 0 25 75 125
No. of foetuses examined 63 89 97 52
Head defects
Encephalocoele 0 0 0 1(1)
Anencephaly 0 0 0 1(1)a/
Cardiac defects
Persistent truncus arteriosus, enlarged aorta,
common entry for aorta and pulmonary artery 0 0 1(1) 1(1)a/
Limb defects
Forepaw flexion, severe 0 1(1) 0 0
Multiple (clubbed feet, shortened forelimbs) 0 0 0 1(1)a/
Vertebral column defects
Fused vertebra 0 0 1(1) 0
Multiple defects 0 1(1) 0 3(2)a/
* Number in parenthesis is number of litters affected
a/ Same foetus
Table 2B. Malformations in rabbits in teratology study with paclobutrazol
Number of foetuses (litters)* affected
mg/kg/day 0 25 75 125
Number of foetuses examined 109 129 103 106
Head defects
Encephalocoele, cleft palate,
gross malformation of skull 0 0 1(1) b/ 0
Cardiac defects
Persistent truncus arteriosus,
enlarged aorta, reduced pulmonary artery 1(1) 4(3) a/ 0 0
Umbilical hernia 0 0 1(1) 0
Limb defects
Forepaws extremely flexed 1(1) 0 2(2) b/c/ 4(3)
Vertebral column defects
Scoliosis 0 0 0 1(1)
* Number in parenthesis is number of litters affected
a/ One also had persistent ductus arteriosus
b/ Same foetus
c/ One also had malrotation of a hind limb
Short-tens studies
Dogs
Groups of one male and one female beagle dogs/dose level
(16-18 weeks old) were given paclobutrazol (91.9% pure) in gelatin
capsules at dose levels of 0, 15, 75 and 225 mg/kg bw/day daily before
feeding for 6 weeks. No treatment-related effects were observed with
respect to clinical condition, body weights, food consumption,
haematology, urinalysis, or histopathological observations. There were
increased plasma alkaline phosphatase activities in the female at
75 mg/kg bw/day and both sexes at 225 mg/kg bw/day. Liver/body weight
ratios were increased in the male at 75 mg/kg bw/day and both sexes at
225 mg/kg bw/day. These changes were probably adaptive rather than
indicative of toxic effects and 225 mg/kg can be taken as a NOAEL for
this study (Clapp et al., 1983).
Table 3. Results of acute toxicity assays with paclobutrazol a/
LD50
Species Sex Route (mg/kg bw) Reference
Mouse M oral 490 Barber & Parkinson, 1982
F oral 1219 " "
Rat M oral 1945 " "
F oral 1336 " "
Guinea pig M oral 542 " "
F oral 400-640 " "
Rabbit M oral 835 " "
F oral 937 " "
Rat M & F dermal >1000 " "
M & F dermal >2000 b/ Pritchard, 1984
Rabbit M & F dermal >1000 Barber & Parkinson, 1982
Rat M i.p. 160-250 " "
F i.p. 99 " "
a/ 97.0% pure unless otherwise specified
b/ 92.4% pure
Groups of six beagle dogs/sex/dose level (22-29 weeks old) were
given paclobutrazol (92.4% pure) in gelatin capsules at dose levels of
0, 15, 75 or 300 mg/kg bw/day daily for one year. One of the control
dogs and one at 15 mg/kg bw/day received each others' capsules for 16
days during weeks 8-10. There were no deaths and no signs of toxic
effects or ophthalmoscopic changes. At 300 mg/kg bw/day body weight
gains were lower than in controls, particularly in the males. No
effects were observed on food consumption or haematological or urinary
parameters. Serum alkaline phosphatase activity was increased in both
sexes given 75 or 300 mg/kg bw/day. Liver weights were increased at
these two dose levels and hepatic aminopyrine-N-demethylase activity
was also increased in both sexes at these dose levels. Histo-
pathological lesions of liver were minimal (mild hepatocellular
swelling in a few males and an increased incidence of slight
ballooning of hepatocytes in females). The liver effects may have been
adaptive rather than toxic. While 15 mg/kg bw/day was a clear NOEL in
this study, 75 mg/kg bw/day can be accepted as a NOAEL (Clapp
et al., 198a).
Long-Term studies
See under "Special studies on oncogenicity".
COMMENTS
Paclobutrazol, administered orally to rats and dogs, was rapidly
absorbed and excreted in urine and faeces. Tissue residues were found
only in liver and kidney and declined rapidly after single or repeated
dosing.
In rats most of the material excreted was in the form of
metabolites. The metabolic pathway was a two-stage oxidation process
of the tertiary butyl moiety. Oxidation to the diol 5-(4-chlorophenyl)-
2,2-dimethyl-4-(1H-1,2,4-triazol-1-yl)pentane-1,3-diol was followed
either by excretion or further oxidation to 5-(4-chlorophenyl)-
3-hydroxy-2,2-dimethyl-4-(1H-1,2,4-triazol-1-yl) pentanoic acid. Males
had a greater capacity to oxidize paclobutrazol than females.
Paclobutrazol is of slight to moderate acute toxicity to mice,
rats, guinea pigs and rabbits.
A one-year study in dogs showed decreased body-weight gains and
liver effects at 300 mg/kg bw/day. Adaptive liver change was the only
effect observed at 75 mg/kg bw/day. In a two-year study in rats
reduced body-weight gains and liver effects were observed at the
highest dose level tested: 1250 ppm. A two-year study in mice also
showed liver effects at the highest dose level tested: 750 ppm. There
was no evidence of oncogenicity in either rats or mice.
There were four negative (two in vitro, two in vivo) and two
equivocally positive mutagenicity assays. The equivocal studies were
the mouse micronucleus test and the in vivo cytogenetics assay in
rats, both of which assayed bone marrow.
Paclobutrazol did not affect fertility or reproductive
performance of rats at doses which produced some maternal toxicity.
Equivocal teratogenic effects were observed in both rats and rabbits,
with cleft palate observed at doses of 240-250 mg/kg bw in rats (in
two studies) and skeletal malformations (multiple vertebral defects
and forelimb flexure) at a dose of 125 mg/kg bw in rabbits. No-effect
levels were demonstrated in both species.
TOXICOLOGICAL EVALUATION
Mouse: 125 ppm in the diet, equal to 15 mg/kg bw/day
Rat: 10 mg/kg bw/day (based on foetotoxicity)
Dog: 75 mg/kg bw/day
ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN
0-0.1 mg/kg bw
STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED
EVALUATION OF THE COMPOUND
Observations in man.
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See Also:
Toxicological Abbreviations