Diboron calcium tetraoxide

Endpoint summary

Description of key information

Numerous studies have demonstrated the toxicokinetics of boric acid and borate salts in humans and experimental animals. At physiological pHs in the aqueous layer of mucosal surfaces, prior to absorption, simple inorganic borated salts are hydrolysed to undissociated boric acid, which are readily absorbed via oral and inhalation exposure. Boric acid is not expected to hydrolyse/react further due to the high energy required to break the B – O bond. Therefore, it is expected that there will be negligible parent compound, calcium metaborate, available systemically and boric acid will be the dominant and common compound in humans and experimental animals. Therefore, a read-across approach using boric acid data is considered appropriate to use, refer to Section 13.

According to an OECD Guideline 401 (Acute Oral Toxicity) in male rats an oral LD50 value for the source substance, anhydrous boric acid, was established >2600 mg/kg bw. According to a standard acute oral study method, conducted pre-GLP, the LD50 values of boric acid in male and female albino rats were 3450 and 4080 mg/kg bw, respectively, the mean LD50 was 3765 mg/kg bw.

According to a FIFRA (40 CFR 163) acute dermal study in male and female New Zealand White rabbits a dermal LD50 value for the source substance, boric acid, was established >2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Please refer to justification attached in section 13.

Reason / purpose for cross-reference:

read-across source

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 600 mg/kg bw

Based on:

test mat.

Remarks on result:

other: There were no deaths at this dose level.

Interpretation of results:

GHS criteria not met

Conclusions:

A single oral administration of anhydrous boric acid to groups of five fasted rats at dose levels of 1540 or 2600 mg/kg resulted in no deaths. The acute median lethal oral dose was therefore considered to be greater than 2000 mg/kg bw.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not specified

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

not specified

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Crl:CD.BR

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate
- Age at study initiation: 5 - 8 weeks of age
- Weight at study initiation: 142 - 217 g
- Housing: Up to 5 rats were accommodated in suspended stainless steel mesh cages (dimensions 55 x 34 x 20 cm). The cages were suspended over carboard lined trays for collection of excreta. The liners were replaced at least twice weekly.
- Diet: Ad libitum except during fasting period
- Water: Ad libitum
- Fasting period before study: 18 h prior to dosing until 3 h after dosing
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25 C
- Humidity (%): 40 - 70 % relative humidity
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12 dark/light; typically 0600 to 1800 h.

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Amount of vehicle: 10 mL/kg
- Lot/batch no.: 1132


MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg


DOSAGE PREPARATION: All formulations were used on the day of preparation.

Doses:

1540 and 2600 mg/kg

No. of animals per sex per dose:

5 males per dose

Control animals:

no

Details on study design:

No data

Statistics:

No data

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 600 mg/kg bw

Based on:

test mat.

Remarks on result:

other: There were no deaths at this dose level.

Mortality:

No animal died following administration.

Clinical signs:

other: No clinical signs were observed for animals dosed at 1540 mg/kg. Piloerection was apparent from approximately 15 min after dosing and for the remainder of Day 1, for all 5 males dosed at 2600 mg/kg. Two rats were lethargic three hours after dosing and on

Gross pathology:

No macroscopic changes were observed during necropsy of Day 15 for animals at 2600 mg/kg.
Isolated changes seen in two rats dosed at 1540 mg/kg included a few red foci on the thymus (animals no 677) and pale lungs and distension of the jejunum (animal No. 678).

Other findings:

No data

Clinical signs following treatment at dose level 2600 mg/kg:

Clinical sign	Animal No.					Time of first observation	Time of recovery
	675 M	658 M	659 M	660 M	661 M
Pilo-erection	+	+	+	+	+	0.25 h	Day 2
Lethargy	-	+	-	+	-	3 h	Day 2
Tachypnoea	-	+	-	-	-	3 h	Day 2

+/- = sign present or absent

Interpretation of results:

GHS criteria not met

Conclusions:

A single oral administration of anhydrous boric acid to groups of five fasted rats at dose levels of 1540 or 2600 mg/kg resulted in no deaths. The acute median lethal oral dose was therefore considered to be greater than 2000 mg/kg bw.
Based on the results of this study, the general Classification and Labelling Requirements for Dangerous Substances and Preparations, as stated in Annex IV to Commission Directive 93/21/EC, indicate that no risk phrase is required for anhydrous boric acid in respect of its acute oral toxicity.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Please refer to justification attached in section 13.

Reason / purpose for cross-reference:

read-across source

Sex:

female

Dose descriptor:

LD50

Effect level:

4 080 mg/kg bw

Based on:

test mat.

95% CL:

>= 3 640 - <= 4 560

Sex:

male

Dose descriptor:

LD50

Effect level:

3 450 mg/kg bw

Based on:

test mat.

95% CL:

>= 2 950 - <= 4 040

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral LD50 of boric acid for male albino rats was 3450 (2950 - 4040) mg boric acid/kg, equivalent to 604 mg B/kg bw. In female albino rats the acute oral LD50 of boric acid was 4080 (3640 - 4560) mg boric acid/kg, equivalent to 714 mg B/kg bw.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards with acceptable restrictions.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Boric acid was administered orally by gavage to six groups of five male and five female albino Sprague-Dawley rats. The test material was administered as a 50 % w/v suspension in 0.5 % aqueous methyl cellulose at dosage levels of 2.0; 2.5; 3.16; 3.98; 5.01 and 6.31 g/kg bw. Rats were fasted for a period of 3 to 4 h prior to dosage. Animals were observed for mortality and toxic effects at 1, 2, 4, and 24 h and once daily after for a total of 14 days. At the end of the observation period the surviving animals were weighed sacrificed and autopsies were performed.

GLP compliance:

no

Remarks:

Study pre-dates GLP

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: Males: 267 - 302 g; Females: 214 - 248 g

Route of administration:

oral: gavage

Vehicle:

other: 0.5 % aqueous methyl cellulose

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50 % w/v

MAXIMUM DOSE VOLUME APPLIED: 3450 - 4080 mg/kg bw

Doses:

2.0; 2.5; 3.16; 3.98; 5.01 and 6.31 g/kg bw.

No. of animals per sex per dose:

Five animals/group; no further data

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs

Statistics:

Litchfield and Wilcoxon

Sex:

male

Dose descriptor:

LD50

Effect level:

3 450 mg/kg bw

Based on:

test mat.

95% CL:

2 950 - 4 040

Remarks on result:

other: mg boric acid/kg

Sex:

female

Dose descriptor:

LD50

Effect level:

4 080 mg/kg bw

Based on:

test mat.

95% CL:

3 640 - 4 560

Remarks on result:

other: mg boric acid/kg bw

Mortality:

No data

Clinical signs:

other: Symptoms include sings of CNS depression, ataxia, convulsions, laboured breathing or rapid respiration; blood crust around nose, marked diarrhoea and ptosis.

Gross pathology:

Autopsies indicated congestion of lungs, kidneys and adrenals; inflammation of the pyloric portion of stomach and small intestine.

Other findings:

No data

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral LD50 of boric acid for male albino rats was 3450 (2950 - 4040) mg boric acid/kg, equivalent to 604 mg B/kg bw. In female albino rats the acute oral LD50 of boric acid was 4080 (3640 - 4560) mg boric acid/kg, equivalent to 714 mg B/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 765 mg/kg bw

Quality of whole database:

The read-across study is reliable with restrictions

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Please refer to justification attached in section 13.

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Interpretation of results:

GHS criteria not met

Conclusions:

The study was performed according to FIFRA (40 CFR 163). The LD50 >2000 mg/kg bw indicating no acute dermal toxicity. No deaths occurred. Clinical changes were limited to erythema, oedema, atonia, desquamation, necrosis and some incidences of skin irritation at more than 24 h of treatment.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

other: FIFRA (40 CFR 163)

Deviations:

no

GLP compliance:

no

Remarks:

Study pre-dates GLP

Test type:

fixed dose procedure

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan F. Plummer
- Weight at study initiation: 1623 - 2922 g

Type of coverage:

semiocclusive

Vehicle:

physiological saline

Details on dermal exposure:

TEST SITE
- Area of exposure: The skin of all animals was abraded longitudinally every 2 - 3 cm, deep enough to penetrate the stratum corneum, but not cause bleeding.
- % coverage: > 10 % of body surface implied
- Type of wrap if used: Semi occlusive


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Moist towel
- Time after start of exposure: 24 h


TEST MATERIAL
- For solids, paste formed: Yes


VEHICLE
- Amount applied: Substance moistened with 1.5 mL saline

Duration of exposure:

24 h

Doses:

Dosage to 2 g/kg

No. of animals per sex per dose:

5/sex/group

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs, histopathology

Statistics:

Not applicable - limit test.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred

Clinical signs:

other: Clinical changes were limited to transient diarrhoea in 2 rabbits and some incidences of erythema (9), and oedema (30), atonia (2), desquamation (4), necrosis, and other evidence of irritation at 23 and ~70.5 h after treatment.

Gross pathology:

No gross necrospy findings were observed. Observations included one animal with gas filled intestine, one animal with pale yellow-coloured kidneys and 5 animals with enlarged or swollen fallopian tubes.

Other findings:

No data

Gross necropsy findings in male and female rabbits at the end of the observation period:

Gross Necropsy Findings	Dosage at 2 g/kg
Number of animals necropsied	10
No gross necropsy findings	5
Intestine
Gas-filled	1
Kidneys
Pale yellow coloured	1
Fallopian tubes
Enlarged or swollen	4
Pale	1
External
Diarrhoea stains	1

Interpretation of results:

GHS criteria not met

Conclusions:

The study was performed according to FIFRA (40 CFR 163). The LD50 > 2000 mg/kg bw indicating no acute dermal toxicity. No deaths occurred. Clinical changes were limited to erythema, oedema, atonia, desquamation, necrosis and some incidences of skin irritation at more than 24 h of treatment.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The read-across study is reliable without restriction

Justification for classification or non-classification

The source substance, boric acid, is not classified for acute oral toxicity as the LD50 values exceed the limits of classification; therefore, according to Regulation (EC) No. 1272/2008 no classification for acute oral toxicity is required for the target substance.

No mortality was observed in the acute dermal study for the source substance, boric acid, therefore in accordance with Regulation (EC) No. 1272/2008 no classification for acute dermal toxicity is required for the target substance.