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Description of key information

According to REACH Annex VIII 8.6.1 and Annex IX 8.6.2, Column 2, repeated dose toxicity studies need not be conducted if a substance undergoes immediate disintegration and there are sufficient data on the cleavage products (both for systemic effects and effects at the site of uptake).  Based on the instant hydrolysis of Trimethyl borate to release boric acid (see IUCLID section 5.1.2 and analogue approach rationale in section 13), repeated dose toxicity information from its hydrolysis product boric acid is taken forward for hazard characterisation of systemic effects. Local effects after repeated oral exposure are not relevant for the safety assessment of Trimethyl borate, as it is only used in industrial settings without oral exposure.
A number of sub-chronic and chronic studies on boric acid and disodium tetraborate decahydrate were carried out in rats, mice and dogs. In some cases these studies are research studies (Weir and Fisher, 1972; Dixon et al, 1976; Seal and Weeth, 1980; Lee et al., 1978; Treinen and Chapin, 1991; Ku et al., 1993), but most support that boron can cause adverse haematological effects and that the main target organ of boron toxicity is the testis.
The NOAEL is equivalent to 17.5 mg B/kg bw/day, 100 mg boric acid/kg bw /day and 168.18 mg C3H9BO3/kg bw/day, respectively.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
168.18 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

According to REACH Annex VIII 8.6.1 and Annex IX 8.6.2, Column 2, repeated dose toxicity studies need not be conducted if a substance undergoes immediate disintegration and there are sufficient data on the cleavage products (both for systemic effects and effects at the site of uptake). Based on the instant hydrolysis of Trimethyl borate to release boric acid (see IUCLID section 5.1.2 and analogue approach rationale in section 13), repeated dose toxicity information from its hydrolysis product boric acid is taken forward for hazard characterisation.

A number of studies on boric acid or disodium tetraborate decahydrate in diet or via drinking water for periods of 30 days to two years in rats, mice and dogs are available, however, the majority of these studies do not comply with current test guidelines, and they lack essential information regarding e.g. histological descriptions and statistical evaluations of the results. Most studies support that boron can cause adverse haematological effects and that the main target organ of boron toxicity is the testis. Other effects observed at high doses include rapid respiration, hunched position, bloody nasal discharge; urine stains on the abdomen, inflamed bleeding eyes, desquamation and swollen paws and tail, reduced food consumption and body weight gain. Treatment with boric acid and disodium tetraborate decahydrate disrupted spermiation, induced degeneration of testicular tubules and caused testicular atrophy. For effects on the blood system extramedullary haematopoiesis, reduced red cell volume and haemoglobin values and deposition of haemosiderin in spleen, liver and proximal tubules of the kidney were described. Several cases of anaemia have been observed in human poisoning cases. However, although doses in these poisoning cases are difficult to define, the effects occurred generally at relatively high concentrations.

Boric acid, the main species present under physiological conditions, acts as a Lewis acid and as such owns the ability to complex with hydroxyl, amino and thiol groups from diverse biomolecules, like e.g. carbohydrates and proteins (BfR, 2006). Such a mechanism could be involved in effects of boron on different enzyme activities (Huel et al., 2004).

A NOAEL for effects on testes and the blood system of 17.5 mg B/kg bw/day can be derived (with a LOAEL of 58.5 mg B/kg bwday) from two 2-year studies in rats on boric acid and disodium tetraborate decahydrate (Weir, 1966a,b).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Weight of evidence consideration from multiple subchronic and chronic studies on analogous substances. The NOAEL of 100 mg/kg bw for boric acid corresponds to 168.18 mg/kg bw for trimethyl borate.

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: testes

Justification for classification or non-classification

Trimethyl borate or boric acid does not meet the CLP criteria for STOT RE classification.