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EC number: 203-016-8
CAS number: 102-24-9
TMBX is hydrolytically unstable and breaks down to form methanol and
boric acid in the presence of water, these species can be expected to be
found in the body fluids and tissues following absorption by any route
of administration. Therefore, an assessment of repeat dose toxicity was
conducted taking account of the hydrolysis breakdown products of TMBX.
A number of sub-chronic and chronic studies on boric acid and disodium
tetraborate decahydrate were carried out in rats, mice and dogs. Most
support that boron can cause adverse haematological effects and that the
main target organ of boron toxicity is the testis. The
NOAEL for fertility effects is equivalent to 17.5 mg B/kg bw/day that
corresponds to NOAEL of 100 mg Boric Acid/kg bw (Weir, 1966a, b).
A reliable oral NOAEL for methanol toxicity following repeated exposure
is not available. A LOAEL of 2340 mg/kg bw/day resulted from a study in
monkeys where all the subjects died within 3 days of the initial dosing
(Rao et al, 1977).A further oral repeat dose study in monkeys
(Martin-Amat et al, 1977), which examined the ocular toxicity following
an initial dose of 2000 mg/kg bw on day 1 followed by 500 mg/kg at
varying intervals did not allow a NOAEL to be derived, despite producing
ocular lesions over the course of the study.
most appropriate point of departure following repeated oral exposure is
based on the NOAEL for Boric acid of 17.5 mg B/kg bw day, an equivalent
NOAEL for TMBX of 93.73 mg/kg bw/day can be derived.
While acute methanol toxicity in monkeys (after a single dose) does not
yield ocular signs, repeated dosing succeeded in producing ocular
lesions (Martin-Amat et al, 1977).
The only detectable ocular change was optic disc edema (of the optic
papilla) which was similar to that seen in raised intracranial pressure
in humans, but without this pressure after methanol (Hayreh et al,
1977). The primary sites of ocular injury were the optic nerve heads and
the anterior segment of the optic nerve rather than the retinal ganglion
cells themselves. It appears that interference with oxidative
phosphorylation causes mitochondrial damage, thus disruption of active
axoplasmic flow in the retrolaminar optic nerve (Baumbach et al., 1977;
Hayreh et al., 1977). [note: In humans it has been hypothesized that
optic atrophy, which often follows acute methanol intoxication, is
secondary to injury of the retinal ganglion cells.]. Mechanistically,
there is a close causal relationship between the prolonged increase in
formic acid from methanol and the development of optic edema. Similar
effects can be produced by intravenous administration of formate without
acidosis (Martin-Amat et al., 1978).
2340 mg/kg bw was the lethal dose for all 7 animals under test after 3
number of animals examined
Mortality at 104 weeks
body weight gain
0-104 weeks (g)
at week 52 (g/kg/day)
at 26 weeks
testes weight (g)
at 104 weeks
Testes atrophy at 24 months
Summary of haematological data from 2 year rat study boric acid:
Cell Volume (%)
Hb Value (g/100 mL)
WBC Count (x103/cm2)
RBC Count (x103/cm2)
* Significantly different from controls
Missing data not thought to be significant according to the summary of
acid is classified under the 1stATP to CLP as Repr. 1B;
H360FD, consequently TMBX also warrants a similar classificaiton based
upon the hydrolysis products previously described.
systemic target organ toxicity after repeated exposures (STOT-RE), boric
acid , and hence TMBX, does not meet criteria for classification and
labelling according to EU CLP Regulation (EC) No. 1272/2008) because no
other than testis target organs were identified during the study (Weir,
Chronic studies in monkeys clearly
demonstrate the potential of the hydrolysis product, methanol to cause
myocardial effects, but these studies were
conducted at a much longer daily exposure time than ususal.
Therefore it is conceivable, that the
observed effects were more severe than in comparable studies
with shorter daily exposure times because
the biologically available dose of methanol was much higher.
Inhalation of TMBX is also unlikely based
upon its anticipated use patterns.
Furthermore, the different susceptibilities
of primates and rodents have to be considered.
Although there is a clear potential of
methanol, and consequently TMBX, to cause adverse health effects
especially in primates,
the experimental studies in non-primates do
not provide clear evidence for the necessity for classification.
Methanol, and by extension TMBX, is
classified as acute toxic by oral, dermal and inhalative exposure, and
of inducing serious irreversible effects
upon single exposure by the oral, dermal and inhalation route thus
making classification for repeat dose toxicity redundant.
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