Calcium metaborate (Ca(BO2)2) and calcium tetraborate (CaB4O7), amorphous reaction products of boric acid with lime

Endpoint summary

Description of key information

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.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

No data

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Does not meet important study design or analytical criteria.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

yes

Remarks:

A non-rodent species

GLP compliance:

no

Remarks:

Study pre-dates GLP

Limit test:

no

Species:

dog

Strain:

Beagle

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0.033, 0.067 and 0.2 % dietary level
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
These concentrations provided doses of 0, 1.7, 3.8, and 10.9 mg B/kg/day, based on the actual body weight and food consumption data in the study.
Basis:

Remarks:

Doses / Concentrations:
Others in the scientific literature have described these doses as 0, 1.5, 2.9, and 8.8 B/kg/day, but these calculations are based on standard assumptions regarding body weight and food consumption, not on the actual data from this study.
Basis:

Remarks:

Doses / Concentrations:
Food consumption was ad libitum.
Basis:

No. of animals per sex per dose:

4/sex/dose

Control animals:

yes, concurrent no treatment

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Dose descriptor:

LOAEL

Effect level:

0.2 other: %

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: SGOT-SGPT values were reversed at the one-year interval.

Dose descriptor:

LOAEL

Effect level:

29 - 120 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LOAEL

Effect level:

5.1 - 21 mg/kg bw/day (nominal)

Based on:

element

Sex:

male/female

Dose descriptor:

LOAEL

Effect level:

29 - 85 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Dose descriptor:

LOAEL

Effect level:

5.1 - 15 mg/kg bw/day (nominal)

Based on:

element

Sex:

male

Dose descriptor:

LOAEL

Effect level:

34 - 120 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Dose descriptor:

LOAEL

Effect level:

6 - 21 mg/kg bw/day (nominal)

Based on:

element

Sex:

female

Critical effects observed:

not specified

Conclusions:

The appearance, behaviour, appetite and elimination for the dogs in all of the dietary test levels were generally comparable with those of the controls and were within normal limits. All maintained or gained weight during the study. The haematological and biochemical values in the test dogs were in general comparable with the control and within normal limits. The SGOT-SGPT values were reversed in the male dogs of all three test levels at the one-year interval and in one male and one female in the 0.2 % group sacrificed at two years. Necropsy findings, terminal body weights, organ/body weights and organ/body weight ratios were observed to be generally within normal limits. There were no histological alterations.

Endpoint conclusion

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

chronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

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).

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

Justification for classification or non-classification

Read across repeat dose toxicity studies from boric acid indicate that the testes are adversely effected following repeated exposure to high doses of boric acid. These data, in combination with intended use conditions, is used to evaluate the potential of the substance to cause target organ toxicity. The registered substance is expected to have predictable adsorption, distribution, metabolism and excretion based on boric acid, meeting the criteria for inclusion.

Boric acid is classified under the 1^stATP to CLP as Repr. 1B; H360FD.

However, text of the 30th ATP as published in the EU Official Journal, 15 September 2008 stated that“The classification and labelling of the substances listed in this Directive should be reviewed if new scientific knowledge becomes available. In this respect, considering recent preliminary, partial and not peer-reviewed information submitted by industry, special attention should be paid to further results of epidemiological studies on the Borates concerned by this Directive including the ongoing study conducted in…”

While boron has been shown to adversely affect male reproduction in laboratory animals, there was no clear evidence of male reproductive effects attributable to boron in studies of highly exposed workers (Whorton et al. 1994; Sayli 1998, 2001; Robbins et al. 2010; Scialli et al. 2010).Not only are these the most exposed workers, but the Chinese worker study is themost sensitive study that has been carried out as semen analysis was performed, a very sensitive detection system for testicular damage.There is no evidence of developmental effects in humans attributable to boron in studies of populations with high exposures to boron (Tuccar et al 1998; Col et al. 2000; Chang et al. 2006).

Several studies in laboratory animals and in vitro studies have recently been completed that demonstrate the protective effect of zinc against boric acid related developmental and fertility toxicity of boric acid. Humans have intrinsically higher levels of zinc than laboratory animals that explain in part the absence of boric acid related reproductive toxicity effects in humans. These studies provide important mechanistic data on the effects of zinc on boric acid related reproductive toxicity that raises doubt about the relevance of the effects for humans. These data provide further justification that classification of Repr. Category 2 H361d is more appropriate for boric acid than Repr. Category 1B H360FD.

Therefore, based on a total weight of evidence, Category 2 H361d: suspected human reproductive toxicant., suspected of damaging the unborn child is considered the appropriate classification. Extensive evaluations of sperm perameters in highly exposed workers have demonstrated no effects on male fertility. While no developmental effects have been seen in highly exposed populations, epidemiological studies of developmental effects are not as robust as the fertility studies, warranting the Category 2 H361d. Regarding systemic target organ toxicity after repeated exposures (STOT-RE), boric acid 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, 1966).