Boron, (acetonitrile)trifluoro-, (T-4)-

Endpoint summary

Description of key information

The LD50 (oral) of acetonitrile in mice was 617 mg/kg bw (BP Chemicals, 1998). The LC50 (4 h) is 1210 mg/m3 in rats with boron trifluoride dihydrate (Rusch et al., 1986). Animals mainly exhibited typical clinical signs of respiratory distress. All respiratory effects were reversible.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study;

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

no

Species:

mouse

Strain:

other: Crl:CD-1 (ICR) BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Portage, MI.
- Age at study initiation: 6-8 weeks of age.
- Weight at study initiation: 24-33 g (m); 19-28 g (f)
- Housing: The animals were housed 3-4 per cage for the first few days of the acclimation period in order to become accustomed to the automatic watering system, then were housed individually in stainless-steel cages.
- Diet: Certified Rodent Chow® #5002, PMI Feeds, Inc., St. Louis, Missouri was available ad libitum, except during designated fasting periods (3-4 hours prior to dosing and 1-2 hours after dosing).
- Water: Water was available ad libitum.
- Acclimation period: 8-19 days

ENVIRONMENTAL CONDITIONS
- Temperature: 66-77°F (18.9-25 °C)
- Humidity: 34-73%
- Photoperiod: 12 hours fluorescent light

Route of administration:

oral: gavage

Vehicle:

other: distilled water

Details on oral exposure:

- Rationale for the selection of the starting dose: The 2000 mg/kg dose is specified by regulatory agencies for the limit test. The other doses were selected to produce partial mortalities in order to calculate an LD50.

Doses:

Single dose 300, 500, 650, 900, 1200, 2000 mg/kg.

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed approximately 1, 2, and 4 hours after dosing on the day of test article administration (study day 1). They were then observed twice daily (morning and afternoon) for 13 additional days and once on the day of necropsy. Individual body weights were obtained just prior to test article administration, on study day 8, at study termination (study day 15), or when an animal was found dead.
- Necropsy of survivors performed: yes, A gross necropsy was performed on all animals dying on study as well as those surviving until study termination (study day 15). For animals surviving until study termination, euthanasia was by carbon dioxide inhalation followed by exsanguination from the abdominal aorta. External abnormalities including palpable masses were examined. Subcutaneous masses were identified and correlated with antemortem findings. Organs were removed and examined and the tissues and carcasses discarded.

Statistics:

The median lethal dose (LD50) and its 95% confidence limits were calculated by the method of Bliss, CI (1938), The determination of the dosage-mortality curve from small numbers. Quarterly Journal of Pharmacy and Pharmacology, 11: 192-216.

Sex:

male

Dose descriptor:

LD50

Effect level:

469 mg/kg bw

95% CL:

>= 163 - <= 699

Sex:

female

Dose descriptor:

LD50

Effect level:

765 mg/kg bw

95% CL:

>= 539 - <= 1 104

Sex:

male/female

Dose descriptor:

LD50

Effect level:

617 mg/kg bw

95% CL:

>= 450 - <= 787

Mortality:

Test article-related combined sex mortalities were 10, 30, 60, 80, 90, and 90% for dose levels 300, 500, 650, 900, 1200, and 2000 mg/kg of acetonitrile (HPLC Grade), respectively. With the exception of the 650 mg/kg group, mortalities were approximately equal for both sexes. No mortalities occurred after study day 2 for any group.

Clinical signs:

other: Significant clinical signs observed during the study included death, tremors, prostration, decreased activity, impaired righting reflex, labored breathing, convulsions, gasping, and increased salivation. All surviving animals were judged normal by study d

Gross pathology:

At necropsy, there were no test article-related findings in any animal.

Interpretation of results:

harmful

Remarks:

Migrated information

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

617 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

1 210 mg/m³ air

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

No experimental data on acute toxicity (oral, inhalation, dermal) with the complex of  boron trifluoride with acetonitrile are available.  Boron trifluoride is classified as skin and eye corrosive and consequently the complex can also be regarded as corrosive, which was confirmed in a Corrositex® - Skin Corrosion Test according to OECD Guideline 435 (see IUCLID section 7.3.1).

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 acetonitrile is extremely water sensitive and reacts even with moist air. In the instantaneous reaction with water as a first step acetonitrile and boron trifluoride dihydrates are formed.
The following studies (read-across) conducted with boron trifluoride dihydrate and acetonitrile further underline the acute toxicity /  corrosiveness of the complex.

Acute oral toxicity:
- Read across to acetonitrile: In a guideline (OECD 401 equivalent) and GLP study, the acute oral LD50 of the read across substance acetronitrile (CAS No. 75 -05 -8) was calculated to be 617 mg/kg for male and female mice combined (with 95% confidence limits of 450-787 mg/kg). Significant clinical signs observed during the study included death, tremors, prostration, decreased activity, impaired righting reflex, labored breathing, convulsions, gasping, and increased salivation. All surviving animals were judged normal by study day 4, with the exception of a single 300 mg/kg group animal that exhibited increased salivation on study day 8.

- Read across to boron trifluoride dihydrate: In a scientifically acceptable non-guideline study (BASF, 1978), boron trifluoride dihydrate (CAS 13319 -75 -0) was administered to male and female Sprague-Dawley rats (5 per sex and dose) orally via gavage at 2.15, 3.16, 4.64 and 6.81 % (v/v) in Lutrol (corresponding to approx. 351, 515, 756 and 1110 mg/kg bw/d). The animals were then observed for 14 days.

Mortality was observed at 351 mg/kg (6/10 after 14 d), 515, 756, and 1110 mg/kg (all: 10/10 after 14 d). Observed clinical signs comprised dyspnea, apathy, staggering, exciccosis and diarrhea. Gross pathology revealed the following findings: heart: acute dilatation bilateral, acute congestive hyperemia; stomach: dilated, liquid content; urinary bladder: in several animals remarkable filling; intestinal mucosa: slight reddened, atonic, diarrheic content. The LD50 was calculated to be 320 mg/kg bw/d.

Acute inhalation toxicity:

- Key / Read across to  boron trifluoride dihydrate:

In a publication of Rusch et al. from 1986, groups (5/sex) of Fischer 344 rats (approx. 7 weeks old) were treated whole body via inhalation route with the read across substance boron trifluoride dihydrate (CAS No. 13319-75-0). Animals were exposed for 4 hours at concentrations of 1.01, 1.22, 1.32 and 1.54 mg/L. Animals were then observed for 14 days. All animals were examined at the end of the chamber equilibration period, at 0.25, 0.5, 0.75 and 1h during exposure, at 0, 1, 2 and 24 h post exposure and daily during the 14-day post-exposure observation period. Body weights were recorded on days 1, 2, 4, 7 and 14. Necropsy was performed on all animals.
Mortality was observed in all dosing groups: 3/10 (1.01 mg/L), 2/10 (1.22 mg/L), 8/10 (1.32 mg/L) and 9/10 (1.54 mg/L). Observed clinical signs 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 study day 6 post exposure.
The LC50 (4 h) was calculated to be around 1210 mg/m3 when rats were whole body exposed by inhalation to aerosols of BF3 dihydrate.

- Supporting / Read across to boron trifluoride dihydrate:
The acute inhalation toxicity of the read across substance boron trifluoride dihydrate (CAS No. 13319-75-0) was evaluated in a 4-hour, single-exposure study in rats according to a protocol comparable to the OECD Guideline 403 (Rusch et al., 2008). The test substance was initially administered to a single group of ten male and ten female Sprague Dawley rats via whole-body exposure at concentrations of 0, 10, 30, 100 mg/m3 (nominal) (8.53±2.83, 24.6±10.3 and 74.4±11.9 mg/m3 (analytical)). All animals were examined at the end of the chamber equilibration period, at 0.25, 0.5, and 1h during 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.
There were no unscheduled deaths. There were no effects on body weight or body weight gain. The larynx showed treatment-related histopathological findings in rats in the 74.4-mg/m3 exposure level group. Based on the results of this study, the LC50 of BF3 was higher than 74.4+/-11.9 mg/m3 when male and female rats were exposed for a single, 4-hour period.

Quite similar LC50 ranges were reported in other publications: LC50 (4 h) of 1180 mg/m3 (Kasparov et al. 1972) and LC50 (1 h) of 899.34 -1439.56 mg/m3 (Vernot et al. 1977), indicating that the substance has a high potential of acute toxicity by inhalation.

The NOAEL for respiratory irritation following a single exposure of 4 hours to low dose levels was estimated around 24.6 mg/m3 (Rusch et al., 2008).

- Supporting / Read across to acetonitrile:

The 4-hour LC50 of the read across substance acetonitrile (CAS no. 75 -05 -8) in mice (via whole-body exposure) was calculated to be 3587 ppm, with 95% confidence limits of 2938-4039 ppm.

Justification for classification or non-classification

Legal classification is available for both read across substances  boron trifluoride and acetonitrile:
Dangerous Substance Directive (67/548/EEC), Table 3.1 List of harmonised classification and labelling of hazardous substances:
- boron trifluoride: T+ (R26: Very toxic by inhalation)
- acetonitrile: Xn (R20/21/22: Harmful by inhalation, in contact with skin and if swallowed.)
Classification, Labelling, and Packing Regulation (EC) No. 1272/2008, Table 3.1 List of harmonised classification and labelling of hazardous substances:
- boron trifluoride:  Acute Tox. 2 (H330: Fatal if inhaled)
- acetonitrile: Acute Tox. 4 (H302 + H312 + H332: Harmful if swallowed, in contact with skin or if inhaled)

[ Separate legal classification of boron trifluoride dihydrate (CAS 13319-75-0) is not available.]

Considering legal classification and study results, the complex of boron trifluoride with acetonitrile should be classified with respect to acute toxicity as follows:

Dangerous Substance Directive (67/548/EEC)

Based on the legal classification under 67/548/EEC of the read across substances  boron trifluoride and acetonitrile and the experimental data available for acetonitrile and boron trifluoride dihydrate, the following classification and labelling is proposed for the test substance:

Xn (R20/21/22: Harmful by inhalation, in contact with skin and if swallowed)

under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EC.

 

Classification, Labelling, and Packing Regulation (EC) No. 1272/2008

Based on the legal classification under Regulation (EC) No. 1272/2008 of the read across substances  boron trifluoride and acetonitrile and the experimental data available for acetonitrile and boron trifluoride dihydrate, the following classification and labelling is proposed for the test substance:
Acute Tox. 4 (H302 + H312 + H332: Harmful if swallowed, in contact with skin and if inhaled)
under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation EC No 605/2014.