BINAPACRYL
EXPLANATION
Binapacryl has been evaluated for an acceptable daily intake
(ADI) by the Joint Meetings in 1969 and 1982 (Annex 1, FAO/WHO, 1970a
and 1983a). A toxicology monograph was prepared by the Joint Meeting
in 1969 (Annex 1, FAO/WHO, 1970b). In 1969 the Joint Meeting estimated
an ADI of 0-0.0025 mg/kg b.w., based on toxicity data largely produced
by IBT. In the absence of any validation or information concerning
replacement studies, the 1982 Joint Meeting recommended that the
existing ADI be withdrawn. Since then some IBT studies that were
evaluated by the 1969 Joint Meeting have been submitted with
accompanying validation reports. Moreover, some new studies have also
become available. All these studies are reviewed in this monograph
addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOLOGICAL DATA
Biochemical aspects
Absorption, distribution, excretion and metabolism
Concentrations of radioactive compounds were measured in the
portal blood of rats 2, 4, and 6 hours after oral administration of
2.7 mg/kg b.w. of binapacryl-(phenyl-U-14C) or binapacryl-(acrylic
acid-14C). The active ingredient was not detectable in the portal
blood at any measurement time. Dinoseb (a hydrolytic product of
binapacryl) was extracted as the only radioactive compound from the
blood when binapacryl-(phenyl-U-l4C) was administered. On average,
15% of the total radioactivity in the blood was extractable as free
dinoseb with diethyl ether. After boiling for 1 hour with 1 M HC1 an
additional 20% of the radioactivity was extracted and also identified
as dinoseb. The remaining radioactivity could not be extracted; it
probably consists of highly polar metabolites which are not hydrolysed
under the conditions adopted. The dimethyl acrylic acid group was
present in the portal blood at a lower concentration than the dinoseb
moiety. In both tests the highest radioactivity in the portal blood
was measured 4 hours after administration (Kunzler et al., 1980).
Dinoseb, dinoseb acetate, binapacryl-(phenyl-U-l4C), or
binapacryl-l4C-labelled in the dimethylacrylic acid group, were
administered orally to rats at a dose level of 8.3 µmol/kg b.w. Two,
4 and 6 hours after administration, the portal blood was withdrawn for
analysis and radioactivity was measured. After administration of
dinoseb, dinoseb acetate, or binapacryl-14-C labelled in the phenyl
ring, the total radioactivity directly extractable from the blood was
identified as dinoseb. Additional dinoseb was extracted after
hydrolysis of the blood samples. After administering binapacryl-14-C
labelled in the dimethylacrylic acid group, only small quantities of
radioactivity were absorbed by the blood; these were highly polar in
nature. Dinoseb was most rapidly absorbed and quickly reached the
maximum blood level. Dinoseb acetate reached a blood level similar to
that of dinoseb but with some delay. Both moieties of the binapacryl
molecule were transferred to the blood, but at distinctly slower rates
and at lower levels than when dinoseb or dinoseb acetate was
administered. As the two moieties of the binapacryl molecule (dinoseb
and dimethylacrylic acid) were not present in the blood at equal
levels, the authors assumed that, after slow hydrolysis of binapacryl,
dinoseb and dimethylacrylic acid were absorbed at different rates
(Dorn et al., 1982).
Toxicological studies
Special study on reproduction
An IBT multigeneration study on binapacryl was reviewed by the
Joint Meeting in 1969 (Annex 1, FAO/WHO, 1970b). In this study, groups
of rats (8 males and 16 females) were fed 0, 1, or 50 ppm of
binapacryl for three generations. The reproductive performance, as
measured by the indices of mating, pregnancy, fertility, parturition
and lactation, was not influenced by the feeding with binapacryl.
Neither were the different parameters of the progeny, e.g. litter
size, number of stillbirths, viability, survival and weight of
weanlings. Upon weaning of the F3b litters, gross and histological
examination of several of the animals from all groups did not reveal
any changes attributable to binapacryl (Kennedy and Calandra,
1965a,b,c).
An audit validation for the three IBT reports covering this
three-generation reproduction study in rats was submitted to the Joint
Meeting in 1985. According to this validation, the three-generation
reproduction study in ablino rats is a valid statement of the work
conducted (Ellison, 1979d,e,f).
However, in view of the many important missing data (e.g.
pathological examinations of weanlings, individual animal and litter
data and specifications of the test substance), the Meeting considered
this study not to be adequate.
Special studies on embryotoxicity and teratogenicity
Groups of 11-12 pregnant female New Zealand rabbits received (by
gavage) binapacryl (% a.i. not specified) at a daily-dose level of 0,
0.2, 1.0, or 5.0 mg/kg b.w. on days 6 through 18 of pregnancy. On day
29, dams were sacrificed and the foetuses removed for external,
visceral and skeletal examinations.
Mean feed and water consumption, and body weight and body-weight
gain of dams were comparable between control and treated groups
throughout the pregnancy period.
There were no statistically-significant differences between
control and treated groups with respect to mean value of corpora
lutea, implantations, live and dead foetuses, early and late
resorptions, or live foetal weight. Placenta weight was slightly
decreased in the 5.0 mg/kg b.w. group, but the difference was not
toxicologically relevant because all other findings were normal. Sex
incidence of live foetuses was also comparable between control and
treated groups.
Foetuses with externally visible malformations were one in the
control and one in the 5.0 mg/kg b.w. group. The incidence of skeletal
variations was usual for this strain and comparable among groups. Only
one visceral malformation was observed in the control group. Survival
rate after 6 and 24 hours was greater in the treated groups than in
the control. Absolute organ weight of dams was unremarkable.
Ophtalmological examinations of eyes of the dams and histopatological
examination of the foetal eyes gave no indication of any cataract
development.
The daily no-effect level for embryotoxicity/teratogenicity is
5.0 mg/kg b.w. in this study (Korte and Osterburg, 1980).
Special studies on mutagenicity
Several microbiol assays carried out on binapacryl did not
indicate any mutagenic potential (Table 1).
Special study on cataract formation
An IBT dog study on cataract formation (Cervenka and Kay, 1963)
was reviewed by the 1969 Joint Meeting (FAO/WHO, 1979). This study has
not been validated (Ellison, 1979b).
Table 1. Results of mutagenicity assays on binapacryl
Test organism Test material Range of doses Result Reference
S. typhimurium Binapacryl 4-2,500 No significant Gericke and
TA 1535 % a.i. not µg/plate difference of Wasner,
TA 1537 specified revertants/ 1978
TA 100 plate compared
TA 98 to negative
control*
S. typhimurium Binapacryl 10-10,000 No significant Shirasu
TA 1535 100% a.i. µg/plate difference of et al.,
TA 1537 revertants/ 1980
TA 1538 TA 100 also plate compared
TA 100 20,000 to control*.
TA 98 µg/plate A slight effect
was observed for
TA 100 at 20,000
µg/plate, only
without S-9 mix.
E. coli WP2 hcr Binapacryl 10-10,000 No significant Shirasu
100% a.i. µg/disc difference of et al.,
revertants/plate 1980
compared to
negative control*.
B. subtilis Binapacryl 20-2,000 No induction of Shirasu
H17 Rec+/M45 100% a.i. µg/disk any inhibitory et al.,
rec- zone in either 1980
strain.
* Both with and without S-9 mix.
Acute toxicity
Oral acute toxicity of technical binapacryl has been studied in
several species, whereas dermal acute toxicity has only been assayed
in rats (Table 2). Clinical signs of acute oral intoxication in mice
include decreased spontaneous activity, lying prone, increased
respiratory rate, discharge of yellow urine and diarrhoea. In fatal
cases, death occurrred within 6 hours after dosing, following
additional symptoms of sudden excitation, a rise of body temperature,
Table 2. Acute toxicity assays on binapacryl
LD50
Species Sex Route Test material Vehicle mg/kg b.w. Reference
Mouse M oral Binapacryl techn. gum arabic 1280 Morioka
et al.,1978a
Mouse F oral Binapacryl techn. gum arabic 1650 Morioka
et al.,1978b
Rat Wister F oral Binapacryl techn. starch sol. 325-350 Scholz, 1964
Rat albino F oral Binapacryl techn. starch sol. 220-270 Scholz, 1964
mixed breed
Rat albino F oral Binapacryl techn. starch sol. 220 Weigand,
mixed breed 1964
Rat M oral Binapacryl techn. peanut oil 63 Gaines, 1969
F oral Binapacryl techn. peanut oil 58
Rat F oral Binapacryl starch sol. 421 Scholz and
Kramer, 1972
Rat M dermal Binapacryl techn. xylene 810 Gaines, 1969
F dermal Binapacryl techn. xylene 720
Rat F dermal Binapacryl techn. gum arabic >2000 Morioka,
1978c
Rabbit M+F oral Binapacryl techn. starch sol. 640 Scholz, 1964
Dog M+F oral Binapacryl techn. starch sol. 450-640 Scholz, 1964
salivation, and finally extension of the hind limbs and stiffness of
the body. All the survivors recovered to normal on the next day of
dosing. Weight loss lasted from 1-4 days of the post-dosing period
(Morioka et al., 1978b).
Short-term studies
Rat
An IBT study in which groups of Sprague-Dawley albino rats
(10 males and 10 females/group) were fed diets containing binapacryl
at levels of 2, 10, 50, 250, or 500 ppm for 90 days, was submitted to
the Joint Meeting in 1969 (Kay and Calandra, 1962). However, this
study has not been validated by Ellison (1979c).
Cat
A non-validated cat dietary study is available where groups of 1
male and 1 female domestic cats were administered binapacryl (% a.i.
not specified) in the diet at daily-dose levels of 0, 0.25 and
25 mg/kg b.w. for 2 years (IBT study without number, dated 24 January
1966).
Dog
Groups of mongrel dogs (1 male and 1 female per group) were fed
diets containing binapacryl (purity not specified), at concentrations
of 25 or 50 ppm for 2 years (6 times per week). No control group was
used. Three dogs, fed at 150 ppm, on day 3 of the experiment already
showed paralytic symptoms in the hind legs and reduced feed
consumption; therefore, the feeding at 150 ppm was discontinued. The
25-ppm and 50-ppm levels produced no toxic symptoms. Behaviour, feed
consumption and weight gains of all animals were normal. The
haematological examinations and urinalyses (appearance, colour,
protein and sediment) did not reveal pathological changes. No clinical
chemistry data were available.
Autopsy and histological examination of heart, lungs, liver,
kidneys, stomach, intestine, spleen, adrenals, testicles or ovaries,
and thyroid gland revealed no lesions attributable to the treatment
(Scholz, 1962).
An IBT dog study, where groups of 3 male and 3 female Beagle dogs
were administered orally (gelatin capsules) binapacryl at dose levels
of 0, 0.25, 1.25, 2.50, 5.0, or 25.0 mg/kg b.w/day for 2 years, was
reviewed by the 1969 Joint Meeting (FAO/WHO, 1970). This study was
validated by Ellison (1979a) and reconsidered by this Joint Meeting.
The NOEL in this study was 0.25 mg/kg b.w., but presentation of the
data is unsatisfactory (e.g. no individual animal data are available
as well as no individual gross and histopathological findings).
Therefore, the Meeting did not consider this study to be adequate
(Baran et al., 1966b).
Groups of 4 male and 4 female Beagle dogs were fed diets
containing binapacryl (98.1% a.i.) at levels of 0, 0.5, 3.3, or 20 ppm
for 2 years.
Animals were observed daily for behaviour, general condition,
feed and water consumption and mortality. Body weights were checked
weekly. Reflex tests, ophtalmoscopic examination, noise test, teeth
inspection and visible mucous membranes inspection were conducted at
0, 3, 6, 9, 12, 18, and 24 months. Haematology, clinical chemistry,
urinalysis, bromosulfophthalein (BSP) test and phenolsulfonphthalein
(PSP) test were carried out at 0, 6, 12, 18, and 24 months. At the end
of treatment all animals were sacrificed for gross and histopatho-
logical examinations.
All dogs survived the scheduled end of the study. There was no
treatment-related impairment of general condition, or of feed and
water intake. Mean body weight gain in males and females of the 20-ppm
dietary level was lower than control. Examinations of behaviour,
neurological condition, eyes, hearing ability, teeth and visible
mucous membranes showed no remarkable findings or differences from the
initial status. Relative organ weights, gross or histopathological
findings did not suggest treatment-related effects.
Haematology, clinical chemistry and urinalysis parameters, and
BSP and PSP tests did not show any dose-related differences between
control and treated groups.
The no-effect level in this study was 3.3 ppm in the diet, equal
to 0.22 and 0.20 mg/kg b.w. for males and females, respectively (Brunk
et al., 1981).
Long-term studies
Rat
An IBT study where groups of Charles-River COB rats (30 males and
30 females per group) were fed diets containing binapacryl at levels
of 0, 25, 100 or 500 pppm for 2 years (Wolf et al., 1966) was
reviewed by the Joint Meeting in 1969. This study has not been
validated (Ellison, 1979g).
In another old study, which completes the 2-year rat study
included in the 1969 evaluation, groups of cross-bred albino rats
(20 males and 20 females/treated group; 5 males and 5 females/control
group) were fed diets containing binapacryl (purity not specified) at
concentrations of 0 and 500 ppm for 2 years.
In the treated group, 15 males and 13 females died during the
experiment (3 males and 4 females during the first six months); marked
body weight losses and laboured breathing were observed prior to
death; most of the animals died of putrid bronchitis or pneumonia. No
mortality occurred in the control group. Behaviour and physical
appearance of surviving rats were comparable between groups.
The weight gains of the treated animals were distinctly lower as
compared to those of the control. No effect was observed on
haematology and urinalysis (appearance, colour, protein and sediment)
carried out on 5 males and 5 females every six months and on all
surviving rats at the end of study.
The macroscopic post-mortem examination performed after
termination of the experiment revealed pneumonia and fatty
infiltration of the liver more frequently among treated animals.
Histopathological examinations (heart, lungs, liver, kidneys and
spleen) revealed purulent broncho-pneumonia in treated animals, but
not in the untreated ones, and purulent bronchiectases, haemosiderosis
in the spleen, brownish pigment in the epithelium of renal tubules,
and fatty infiltration in the liver more frequently in the treated
than untreated animals. No tumours were observed (Scholz, 1962).
This study, however, was considered by the Joint Meeting to be
inadequate for several reasons, including the small number of animals
used, the small number of survivors at the end of the study, and the
fact that only five organs were examined histopathologically.
COMMENTS
Additional pharmacokinetic and metabolism studies in rats
indicate that binapacryl is rapidly absorbed following oral
administration and showed that only dinoseb, dimethyl acrylate and
water-soluble metabolites could be measured in the portal blood.
Absorption occurred more slowly with binapacryl than with dinoseb.
This suggests that decomposition of binapacryl to dinoseb occurs in
the gastrointestinal tract.
However, in dogs (study evaluated in 1969), appreciable amounts
of binapacryl were measured in the kidney, liver and brain, which may
be indicative of species differences in metabolism.
Acute toxicity studies did not show any species, strain, or sex
specificity.
A no-effect level was established for embryotoxic/teratogenic
effects in rabbits.
The three-generation reproduction study in rats was not
considered to be valid.
Binapacryl did not show any mutagenic potential in several
bacterial tests.
Paralysis of hind-quarters was observed in dogs fed high
(150 ppm) dietary levels of binapacryl in capsules (1969 evaluations),
but not in a new 2-year dietary dog study at levels comparable with
the capsule study. Paralysis of hind-quarters was not observed in rat
studies at any dose levels.
Apart from the new dog study, the short and long-term studies
submitted do not conform to present-day testing standards. Some of the
studies were considered invalid. None of the long-term studies contain
clinical chemistry examinations.
The Meeting concluded that the total data base is inadequate for
establishing an ADI.
TOXICOLOGICAL EVALUATION
At least the following data will be required before the
assessment of an ADI can be reconsidered:
1. Teratology study in rats.
2. Chronic toxicity/carcinogenicity studies in rats.
3. Carcinogenicity study in a second species.
4. Multi-generation reproduction study.
5. Pharmacokinetic studies.
6. Justification for the small doses administered in the rabbit
teratology study.
7. In studies that were found to be invalid, possible
neurological effects were noted. If these effects are observed in
any of the above studies, they should be investigated further.
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See Also:
Toxicological Abbreviations
Binapacryl (ICSC)
Binapacryl (FAO/PL:1969/M/17/1)
Binapacryl (WHO Pesticide Residues Series 4)
Binapacryl (Pesticide residues in food: 1984 evaluations)