Hydrogen trifluoromethoxyborate(1-), compound with methanol (1:1)

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Similar to all coordination complexes of boron trifluoride with organic and inorganic species (like alcohols, ethers, amines, sulfuric acid, sulfuric dioxide, etc) the complex of boron trifluoride and methanol is extremely water sensitive and reacts even with moist air. Given the extremely rapid decomposition the rate of hydrolysis cannot be quantitatively derived in a study conducted according to OECD Guideline 111. However sufficient information is available on the identity of hydrolysis products which aquatic organisms may be eposed.
In the instantaneous reaction with water as a first step methanol and boron trifluoride dihydrates are formed.
BF3·CH3OH+ 2 H2O -> BF3· 2 H2O + CH3OH
The hydrolysis of borontrifluoride dihydrate was investigated at pH-values of 1.2; 4.0; 7.0 and 9.0 (BASF SE, Study No. 09S01179, 26.19.2009)
The hydrolysis of the test item is a very fast process (half-life < 30 minutes). Already at room temperature about 30 to 60% of the test item was hydrolyzed within minutes in all tested buffer solutions in the pH range 1.2 to 9.0.
The main reactions of the hydrolysis process are the following:
BF3.2H2O + H2O → B(OH)3+ 3HF
HF + BF3.2H2O → HBF4+ 2H2O
B(OH)3+ 4HF → HBF4+ 3 H2O
HBF4+ H2O ↔ HBF3(OH) + HF
Total hydrolysis of HBF4:
HBF4↔ HBF3(OH) ↔ HBF2(OH)2↔ HBF(OH)3↔ HB(OH)4= B(OH)3+ H2O
Boric acid and tetrafluoroborate are expected to be the main species in the dilute hydrolysis solution (Zhang Weijiang et al.).
In conclusion it is justified to base the assessment of environmental fate and pathways of hydrogen trifluoromethoxyborate (1-), compound with methanol (1.1) on the properties of the breakdown products, which is considered acceptable in accordance with REACH Annex XI, section 1.5.
References:
BASF SE, Boron trifluoride dihydrate: hydrolysis as a function of pH, Study No. 09S01179, 26.10.2009
Wamser C. A. Equilibria in the system boron trifluoride-water at 25 °C,Journal of the American Chemical Society, 1951, 73: 409-416
Zhang Weijiang et al., Equilibrium on the hydrolysis of Boron trifluoride in large amount of water,Transactions of Tianjin University, 2016, 22: 486-491


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
boron trifluoride dihydrate (CAS no. 13319-75-0), methanol (67-56-1). For purity and impurities see study records in IUCLID chapter 7.2.2.

3. ANALOGUE APPROACH JUSTIFICATION
The hydrolysis data in IUCLID chapter 5.1.2 demonstrate the rapidity of the hydrolysis reaction. Exposure will never occur to the complex of boron trifluoride methanol but to its hydrolysis products, BF3 dihydrate and methanol. Therefore, these two substances are the relevant ones for evaluation of potential health effects.

4. DATA MATRIX
A data matrix is not applicable in this case. The present read-across approach is not based on the comparison of experimental data for one or more compounds, but the hydrolysis products of the registered material are considered the relevant toxophors due to the rapid hydrolysis reaction. Reliable data are provided for all hydrolysis products, whereby an evaluation of potential health hazards can be performed.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

not specified

GLP compliance:

not specified

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
- Source: Charles River UK, Margate, Kent, UK
- Age at study initiation : 6-7 (males) or 7-8 (females) weeks of age
- Fasting period before study: no
- Housing: in groups of 5
- Diet: ad libitum (SDS Special Diet Services, Witham, England)
- Water: ad libitum (tap water)
- Acclimation period: at least 5 days in the laboratory prior to exposure.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3°C
- Humidity: 50 ± 20%
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

Exposure system
Exposures were conducted in whole-body acrylic exposure units with an internal volume of 120 L.
The air flow was maintained al 29 L/min.
Each rat was housed individually in a stainless-steel mesh cage within the exposure unit.
The liquid aerosol was generated using a stainless steel concentric jet atomizer that typically produced an aerosol with a mass media aerodynamic diameter of between 1 and 4 µm.

Analysis of the Test Atmosphere
At least five samples of the chamber atmosphere were withdrawn during each exposure level.
Samples of known volume were collected on quartz fiIters, then desorbed into a known volume of water containing 0.1 M ammonium fluoride or were drawn through a sintered glass bubbler (gas absorption trap) using 0.1 M ammonium fluoride as the trapping medium.
The concentration was determmed using a BF4 ion selective electrode (Thermo Electron model 93-5 fluorborate half cell electrode; Thermo Electron model 90-02 double junction reference electrode, inner chamber filed with Thermo-Electron 900002 double junction inner filling solution, enter chamber filled with 0.1 M NH4F).
Particle size distribution was measured using a Marple 290 series cascade impactor (model 296, Graseby, Anderson, Inc., Atlanta, GA).
Particle size analysis was conducted twice for the 30- and 100-mg/m3 exposure levels and only once in the 10-mg/m3 exposure level due to the large sample volume required.

BF3 CONCENTRATION
The measured exposure levels were 8.53 (±2.83), 24.6 (±10.3), and 74.4 (±11.9) mg/m3.
Due to the tendency of BF3 to be absorbed onto the exposure chamber walls, the nominal concentrations required to achieve these levels were 319, 734, and 982 mg/m3, respectively. The mass median aerodynamic diameter (MMAD) for the aerosols in the 24.6- and 74.4-mg/m3 exposure levels were 2.3 and 3.3 µm, with a geometric standard deviation (GSD) of 2.42 and 2.61, respectively, indicating that the aerosol was respirable.
In the 8.53mg/m3 exposure level, the MMAD was 0.7 µm with a GSD of 2.27.
The mean temperatures in the chambers during exposure were 23.2 °C (control), 21.0 °C (8.53 mg/m3), 24.1 °C (24.6 mg/m3), and 26.1 °C (74.4 mg/m3).
The mean RH was in the range of 38-40% for all exposures except 8.53 mg/m3, where it could not be determined due to problems with the water vapour analyzer.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

0, 10, 30, 100 mg/m3 (nominal)
8.53±2.83, 24.6±10.3 and 74.4±11.9 mg/m3 (analytical)

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

One group was sacrificed 24 h after exposure and the second was held for a 14-day observation period and then sacrificed.

Parameters Evaluated
All animals were evaluated at the end of the chamber equilibration period, at 0.25, 0.5, and 1h into the exposure, at 0, 1, 2 and 24 h post exposure and twice daily during the 14-day post exposure observation period for those animals not sacrificed 24 h post exposure.
Body weights were recorded daily from pretreatment until sacrifice.
Water consumption was estimated by visual observation of the amount of water consumed by the test and control animals.
At sacrifice, animals were killed by intraperitoneal injection of sodium pentobarbitone, exsanguinated and examined for gross pathological changes.
Lung and kidney weights were determined.
The nasal passages, lungs (including trachea, larynx, and tracheal bifurcation), and kidneys were preserved in 10% neutral buffered formalin, and examined by light microscopy.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 74.4 mg/m³ air (analytical)

Exp. duration:

4 h

Sex:

male/female

Dose descriptor:

other: NOAEL

Effect level:

24.6 mg/m³ air

Exp. duration:

4 h

Remarks on result:

other: Respiratory irritation

Mortality:

There were no unscheduled deaths.

Clinical signs:

other: During the exposure, all animals in all groups appeared normal. One female rat in the 74.4-mg/m3 exposure group exhibited brown staining around the snout and jaws immediately following the exposure. This had resolved after the 1-h post-exposure observati

Body weight:

There were no effects on body weight or body weight gain.

Gross pathology:

Lung and kidney weights appeared normal and there were no remarkable gross necropsy findings.
The larynx showed treatment-related histopathological findings in rats in the 74.4-mg/m3 exposure level group.

The findings were most pronounced in the subgroup sacrificed 24 h post-exposure. These comprised ventral cartilage necrosis, anterior ventral hemorrhage (males only), and an increase in severity of ventral epithelial hyperplasia and one with dyspnea and rates, and one with a thorax filled with fluid prior to death.
The other two rats survived until the scheduled sacrifice but exhibited a slightly reduced body weight gain compared to controls. One of these two rats presented with red lungs and the other with green/brown discolored lungs. Absolute and relative lung weight of these two surviving rats was clearly higher than those in the control and low exposure level groups. No changes in kidney weights were seen in either group.

Other findings:

Water consumption appeared normal.

Cross-reference 2

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Test procedure in accordance with normal standard methods.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

not specified

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Labs (Portage, Mich.)
- Age at study initiation: approximately 7 weeks old
- Fasting period before study: no
- Housing: individually in suspended stainless-steel mesh cages
- Diet: ad libitum Purin Rat Chow 5001
- Water: ad libitum
- Acclimation period: for a minimum of 2 weeks

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

other: air

Details on inhalation exposure:

Exposure Chamber Designs and Operation
The acute exposure was conducted in 225-liter stainless-steel and glass exposure chambers, operated under negative pressure with filtered, conditioned air.
The total flow rate during the acute study was approximately 50 liters/min, providing a t99 equilibration time of 21 min.

Test Atmosphere Generation Procedures
Test atmospheres in the acute study were generated with a Solo-Sphere nebulizer (McGraw Respiratory Therapy, Irvine, CA.) operated with compressed, breathing-grade air. Exposure concentrations were controlled by regulating the airflow through the nebulizer, and thus the rate of aerosol generation.

Analysis of Chamber Concentrations
Nominal aerosol concentrations were determined daily by measuring the amount of test material consumed during the exposure and dividing this by the total airflow through the chamber. At hourly intervals, actual air concentration measurements were made by trapping aerosol samples of known volume in 15-mL impingers, using a flow-Gmiting orifice (Millipore XX50000014) with a pump (Gast DOA-122) and dry test meter (Singer DTM-115-3) for volume measurement. The aerosol was then dissolved in distilled water and analyzed for BF3 content by an ion-selective electrode technique. Sample volumes were varied to permit collection of roughly equal quantities of BF3.
Particle size measurements were made with an Anderson I ACFM particle sizing sampler (Anderson 2000, Inc., Atlanta, Ga.). Measurements were performed hourly during the acute exposures; three times/week during the subacute exposures; and twice each week during the subchronic exposures. The material collected on each stage was determined gravimetrically.
Mass median aerodynamic diameter: 1.8 µm

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

1.01, 1.22, 1.32 and 1.54 mg/L

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

EXAMINATIONS: 
Duration of observation: 14 days
- Clinical signs: examined just before exposure, at 15-minute intervals  during the first hour then hourly for the remaining of exposure and daily until the completion of the study.
- Mortality: idem
- Body weight: measured on days 1, 2, 4, 7 and 14
- Necropsy:
macroscopic examination of the main organs: yes

Sex:

male/female

Dose descriptor:

LC50

Effect level:

1 210 mg/m³ air

Exp. duration:

4 h

Mortality:

Deaths occurred in all exposure groups: nine (out of 10) at 1.54 mg/L,  eight at 1.32 mg/L, two at 1.22 mg/L, and three at 1.01 mg/L, ranging  from the day of the exposure to 6 days post-exposure. 

Clinical signs:

other: Clinical signs elicited by the exposures included dry and moist rales,  gasping, excessive oral and nasal discharge, and lacrimation, indicative of respiratory distress and irritation. Recovery was apparent for the rats surviving beyond 6 days post-exposu

Body weight:

A body weight decrease was recorded.

Gross pathology:

A decrease in liver and kidney weight was noted.

Cross-reference 3

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Secondary literature; no LC50 value indicated. No study in rat.

Principles of method if other than guideline:

Secondary literature source no data about the method was available.

GLP compliance:

not specified

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Route of administration:

inhalation

Duration of exposure:

5.5 h

Concentrations:

135, 350 and 750 ppm

No. of animals per sex per dose:

10

Sex:

not specified

Dose descriptor:

LC100

Effect level:

< 750 ppm

Exp. duration:

5.5 h

Mortality:

A 1.4-hour exposure at 350 ppm resulted in the death of 7 animals. A 10.9-hour exposure at 135 ppm resulted in the death of 1 animal. Deaths were attributed to pulmonary irritation.

Cross-reference 4

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Documentation insufficient for assessment. Original reference is in Russian. Its translation is available but is not detailed enough. Actually this study involves several species (rats, mice and guinea-pigs) and reported results do not precise for each finding which species is concerned. In this IUCLID, all findings are reported.

GLP compliance:

not specified

Species:

other: mouse, rat and guine-pigs

Strain:

not specified

Sex:

not specified

Route of administration:

inhalation

Duration of exposure:

> 2 - <= 4

Remarks on duration:

Rats and guinea-pigs were exposed for 4 h while mice were exposed for 2h.

Concentrations:

no data

Details on study design:

- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Sex:

not specified

Dose descriptor:

LC50

Effect level:

1 180 mg/m³ air

95% CL:

959 - <= 1 451

Exp. duration:

4 h

Remarks on result:

other: rats

Sex:

not specified

Dose descriptor:

LC50

Effect level:

3 460 mg/m³ air

95% CL:

2 900 - <= 4 350

Exp. duration:

2 h

Remarks on result:

other: mice

Sex:

not specified

Dose descriptor:

LC50

Effect level:

109 mg/m³ air

95% CL:

81.5 - 146.3

Exp. duration:

4 h

Remarks on result:

other: guinea pigs

Mortality:

Animals exhibiting previous findings died within 24 hours.

Clinical signs:

other: A marked irritation of ocular mucosa and respiratory troubles were noted. First, turmoil was observed, then an oppression phase with motor  coordination troubles occurred.

Body weight:

Not examined

Gross pathology:

Dead animals exhibited mucosal cynanosis, congestion of internal organs  and encephalic vessels. Moreover, lung presented an increased weight and  haemorraghes. Microscopic examination confirmed lung injuries (important  oedema, alveolar septa destruction. Cardiac and hepatic dystrophy were also noted. Kidneys, spleen and brain exhibited congestion.

Cross-reference 5

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Secondary literature. No LC50 value indicated. No study in rat.

Principles of method if other than guideline:

Secondary literature source no data about the method was available.

GLP compliance:

not specified

Species:

mouse

Strain:

not specified

Sex:

not specified

Duration of exposure:

5.5 h

Concentrations:

135 and 750 ppm

No. of animals per sex per dose:

10

Sex:

not specified

Dose descriptor:

other: LC10

Effect level:

750 ppm

Exp. duration:

5.5 h

Mortality:

No mice died after a 10.9-hour exposure to 135 ppm.

Cross-reference 6

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Secondary literature; no LC50 value indicated.

Principles of method if other than guideline:

Secondary literature source no data about the method was available.

GLP compliance:

not specified

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

inhalation

Duration of exposure:

5.5 h

Concentrations:

135 and 750 ppm

No. of animals per sex per dose:

10

Sex:

not specified

Dose descriptor:

other: LC10

Effect level:

750 ppm

Exp. duration:

5.5 h

Mortality:

No rats died after a 10.9-hour exposure at 135 ppm.

Cross-reference 7

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Secondary literature.

Principles of method if other than guideline:

according to Thompson (1947) and Weil (1952)

GLP compliance:

not specified

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Duration of exposure:

1 h

Concentrations:

no data

No. of animals per sex per dose:

5

Sex:

male

Dose descriptor:

LC50

Effect level:

320 - 467 ppm

Exp. duration:

1 h

Sex:

female

Dose descriptor:

LC50

Effect level:

293 - 469 ppm

Exp. duration:

1 h

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Hydrogen trifluoromethoxyborate(1-), compound with methanol (1:1)

EC Number:

220-543-9

EC Name:

Hydrogen trifluoromethoxyborate(1-), compound with methanol (1:1)

Cas Number:

2802-68-8

Molecular formula:

CH4O.CH3BF3O.H

IUPAC Name:

hydrogen trifluoro(methanolato)borate(1-) methanol (1:1)

Results and discussion

Effect levels

Effect levels 1

Sex:

male/female

Dose descriptor:

LC50

Effect level:

1 210 mg/m³ air

Exp. duration:

4 h

Remarks on result:

other: rat, Rusch et al., 1986

Effect levels 2

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 74.4 mg/m³ air

Exp. duration:

4 h

Remarks on result:

other: rat, Rusch et al., 2008