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Description of key information

All the studies conducted with BF3 (gas) or BF3 dihydrate cause signs of respiratory distress. This effect was already seen in the acute toxicity tests. Furthermore necrosis of the proximal tubuli were observed in some animals. This effect correlates with the increasing amount of fluoride in urine.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
not specified
GLP compliance:
not specified
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
- Weight at study initiation: no data
- Fasting period before study: no
- Housing: individually in suspended stainless-steel mesh cages
- Diet (e.g. ad libitum): ad libitum Purina Rat Chow 5001
- Water (e.g. ad libitum): ad libitum
- Acclimation period: for a minimum of 2 weeks
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle); (aerosols of BF3 dihydrate)
Details on inhalation exposure:
Exposure Chamber Designs and Operation
Subchronic exposures were conducted in 1000-liter stainless-steel and glass exposure chambers, operated under negative pressure, with filtered, conditioned air.
The total air flow rate was approximately 350 liters/min, providing a t99 equilibration time of 13 min. Exposures were conducted for 6 hr/day, 5 days/week for 13 weeks.
Chamber air temperature and relative humidity were monitored at least twice daily with a YSI Model 47 Scanning Tele-Thermometer (Yellow Springs Instrument, Yellow Springs, Ohio) and an Airguide Model 605 humidity indicator (Airguide Instrument, Chicago, Ill.), respectively.
All animals were left in the chambers for a period of at least 30 min immediately following the exposure to allow for equilibration of the chamber atmosphere with clean air.

Test Atmosphere Generation Procedures
Test atmospheres in the subchronic study were generated with a DeVilbiss No. 40 Glass nebulizer (The DeVilbiss Company, Somerset, Pa.) and Sage Model 355 syringe pump (Sage Instruments, Cambridge, Mass.). The nebulizer was operated with compressed, breathing-grade air under conditions that rapidly aerosolized the liquid BF3 2H20. The rate of delivery, and thus the quantity of aerosol produced, was controlled by regulating the feed rate on the syringe pump.

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 on cellulose nitrate membrane filters, 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 (Carlson and Paul, 1968; Gulens and Lesson, 1980). 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 twice each week during the subchronic exposures. The material collected on each stage was determined gravimetrically.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 h/day, 5 d/week
Remarks:
Doses / Concentrations:
0, 2, 6 and 17 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
20
Control animals:
yes
Details on study design:
Post-exposure period in recovery group: 2 weeks (5 animals/sex/dose group)
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: once weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after one month of exposure in 5 animals/sex/dose, during the final week of the exposure period (15 animals/sex/dose) and at two weeks past the final exposure (retained group of five animals/sex/dose).
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- Parameters checked:

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after one month of exposure in 5 animals/sex/dose, during the final week of the exposure period (15 animals/sex/dose) and at two weeks past the final exposure (retained group of five animals/sex/dose)
- Animals fasted: No data
- Parameters checked: blood urea nitrogen (BUN), serum glutamic-pyruvic transaminase (SGPT), alkaline phosphatase, glucose, albumin, total protein, globulin by difference, CA, P, Cl, Na and K

URINALYSIS: Yes
- Time schedule for collection of urine: after one month of exposure in 5 animals/sex/dose, during the final week of the exposure period (15 animals/sex/dose) and at two weeks past the final exposure (retained group of five animals/sex/dose)
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: volume, osmolality, pH and creatinine

OTHER:
In addition, determination of urinary ionic and total fluoride and serum total fluoride amounts was made at 1 and also 2 months of exposure (for urinary ionic and total fluoride only), during the final week of the exposure period and two weeks following the final exposure with the same animals selected for serum chemistry determinations.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC): 
- Weighted organs: brain, heart, kidneys, liver, lungs (with trachea),  ovaries, spleen and  testes 
- Macroscopic and microscopic examinations: Tissues from 40 major organs  of high-exposure and control groups were examined. In  addition, nasal turbinates, kidneys, lungs and liver were examinated  from all other animals of the study.
Statistics:
The results of measurements of all quantitative continuous variables such  as body weight, hematology, and clinical chemistry data were  compared between exposure groups and controls, by the use of the following  tests: Bartlett's homogeneity of variance, analysis of variance, and Duncan's procedure. The latter was  used if F for analysis of variance was significantly high to delineate  which groups differed from the controls.  If Bartlett's test indicated heterogenous variance, the F max test was  used for each group versus the control.  If these individual Fmax tests were not significant or N1 = N2 Student's  t test was used; if significant, the means were compared by the Cochran t  test or the Wilcoxon rank sum test.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS:
There was an increased incidence of dried material around the mouth and  nose, rales and excessive lacrimation, primarily in the high-exposure  group.

MORTALITY: One rat died in the high-exposure group. This death was attributed to the  test substance. Two accidental deaths occurred.

BODY WEIGHT: No differences were observed between treated and control groups.

HAEMATOLOGY: No differences were observed between treated and control groups.

BLOOD CHEMISTRY: An exposure-related depression of total protein concentrations (up to  16%) accompanied by an exposure-related depression of globulin  concentrations (up to 38%) was observed. One male from the high-exposure group had elevated blood urea nitrogen. Serum fluoride concentration were markedly increased in all exposure  groups (dose-related increase). A recovery was noted after the end of  exposure.

URINALYSIS: An exposure-related depression in calcium amounts and an exposure-related increase in urinary fluoride were noted. The decrease in calcium values was found to be reversible at the end of  exposure.

NECROPSY:
- Organ weight: No differences were observed between treated and control groups.
- Macroscopic findings: No specific changes were observed in treated groups when compared to  control group.
- Microscopic findings: In the high-exposed dead male, necrosis of the renal tubular epithelium  was seen. Another high-exposed rat also exhibited such a necrosis (animal with elevated blood urea nitrogen).
Dose descriptor:
NOAEL
Effect level:
6 mg/m³ air
Sex:
male/female
Basis for effect level:
other: kidney effects
Dose descriptor:
LOAEC
Effect level:
17 mg/m³ air
Sex:
male/female
Basis for effect level:
other: Tubular necrosis in 2 male rats
Dose descriptor:
LOEC
Effect level:
2 mg/m³ air
Sex:
male/female
Basis for effect level:
other: Increase of fluorine in urine and in blood samples
Dose descriptor:
LOEC
Effect level:
6 mg/m³ air
Sex:
male/female
Basis for effect level:
other: Minimal findings of respiratory irritation
Critical effects observed:
not specified

MEAN URINARY CALCIUM CONCENTRATIONS (mg/dL)
Exposure (mg/m3) Males Females
Week 5 Week 9 Week 13 Week 15 Week 5 Week 9 Week 13 Week 15
0 7.70 a 12.22 15.12 25.00 10.34 18.44 14.17 40.0
2.49 5.31 11.29 8.99 4.02 5.71 7.57 12.7
3 5 20 5 5 5 20 3
2 8.67 8.36 11.45 25.50 7.24 12.42 9.63 31.8
4.46 3.17 8.90 6.36 2.15 4.99 5.19 14.0
4 5 20 5 5 5 20 5
6 11.18 5.82* 8.01* 19.76 4.22** 6.22** 6.63** 29.5
5.99 1.58 3.68 7.89 1.30 2.52 4.47 18.8
5 5 20 5 5 5 19 4
17 3.38 3.72** 5.95** 19.26 6.75 6.78** 11.67 51.9
2.06 1.10 4.70 12.15 1.98 3.62 7.36 21.7
5 5 19 5 4 5 20 5
a Mean, standard deviation, number of animals evaluated.
* Significantly different from control p< 0.05.
** Significantly different from control p< 0.01.

URINARY FLUORIDE AND TOTAL FLUORINE AMOUNTS
Exposure (mg/m3) Males Females
Week 5 Week 9 Week 13 Week 15 Week 5 Week 9 Week 13 Week 15
Urinary ionic fluoride amounts (µg)                
0 14 a 7 11 5 11 6 11 7
2 5 8 1 2 1 6 6
3 5 20 5 5 4 20 5
2 121 160** 257** 86* 192** 187** 251** 57**
57 62 98 30 59 37 79 19
4 5 20 5 5 5 20 5
6 175* 211** 228** 114** 340** 240** 382** 68**
67 85 104 50 39 83 103 35
5 5 20 5 5 5 20 5
17 418** 430** 412** 140** 409** 346** 453** 64**
82 61 212 79 72 78 144 16
5 5 19 5 4 5 20 5
Total urinary fluorine amounts (µg)                
0 21 17 59 7 10 6 12 8
3 11 56 2 4 1 6 6
5 4 20 5 5 4 20 5
2 166 192 392 111 323 338 360* 64
60 36 155 40 169 80 153 22
4 5 20 5 5 5 20 5
6 506 465 506- 213 805** 595* 811** 119**
188 115 252 80 314 264** 248 70
5 5 20 5 5 5 20 5
17 2201** 2546* 2021** 476** 1766** 1592** 1694** 184**
574 2221 1418 258 435 438 796 47
5 5 19 5 4 5 20 5
a Mean, standard deviation, number of animals evaluated.
*Significantly different from control p< 0.05.
**Significantly different from control p< 0.01.

Exposure (mg/m3) Males Females
Week5 Week13 Week15 Week5 Week13 Week15
Total serum protein (g/dl)            
0 6.24 a 7.29 6.92 6.80 7.15 7.03
0.31 0.27 0.42 0.35 0.17 0.15
5 15 5 5 15 4
2 5.90 6.91 7.18 5.94** 6.79** 7.00
0.26 0.46 0.26 0.50 0.25 0.34
5 15 5 5 15 5
6 6.16 6.89 6.98 6.06 6.74** 6.88
0.29 0.45 0.26 0.34 0.16 0.27
5 15 5 5 15 5
17 6.14 6.56** 6.90 5.74** 6.67** 6.94
0.30 0.65 0.27 0.23 0.20 0.15
5 15 5 5 15 5
Globulin (g/dL)            
0 1.60 2.59 2.06 2.62 2.63 2.93
0.31 0.30 0.21 0.63 0.17 0.28
5 15 5 5 15 4
2 1.56 2.36 2.40 1.88 2.35** 2.94
0.33 0.39 0.14 0.51 0.20 0.42
5 15 5 5 15 5
6 1.78 2.31 2.20 1.86 2.31** 2.78
0.23 0.43 0.26 0.31 0.15 0.15
5 15 5 5 15 5
17 1.86 2.09** 2.30 1.66* 2.27** 2.70
0.25 0.54 0.63 0.49 0.15 0.12
5 14 5 5 15 5
a Mean, standard deviation, number of animals evaluated.
* Significantly different from control p< 0.05.
** Significantly different from control p< 0.01.

TOTAL SERUM FLUORINE AND BONE FLUORIDE
Exposure (mg/m3) Males Females
  Week 5 Week 13 Week 15 Week 5 Week 13 Week 15
Serum total fluorine (µg/mL)            
0 0.21 a 0.27 0.19 0.46 0.28 0.10
0.17 0.16 0.06 0.12 0.09 0.03
5 15 5 5 15 4
2 0.36 0.98 0.38 0.81 2.26 0.29
0.05 0.35 0.10 0.27 0.32 0.14
5 15 5 5 15 5
6 1.04 2.17 1.15* 2.82* 3.46* 0.77
0.23 0.6 0.42 1.33 1.00 0.56
5 15 5 5 15 5
17 3.32* 8.94* 1.65* 5.06* 7.25* 2.97*
1.11 0.69 0.65 0.88 2.97 0.51
5 14 5 5 15 5
Bone fluoride (µg/g)            
0   167 145   157 155
  16 27   56 27
  8 5   14 4
2   758* 905*   1159* 1178*
  180 161   262 179
  12 5   15 4
6   1119* 1430*   1564* 1709*
  165 204   197 63
  15 5   15 5
17   1554* 2109*   2289* 2763*
  183 536   422 364
  14 5   15 5
a Mean, standard deviation, number of animals evaluated.
* Significantly different from control p< 0.01.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
6 mg/m³
Study duration:
subchronic
Species:
rat

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

No study is available for the test substance. Therefore repeated dose toxicity was assessed with the read across substances boron trifluoride and boron trifluoride dihydrate, which is considered acceptable in accordance with REACH Annex XI, section 1.5, as discussed in IUCLID chapter 7.1.


Several studies are available for that endpoint but only one subacute toxicity study and one subchronic toxicity study are of good quality. All studies point out that BF3 (gas) or BF3 dihydrate causes signs of respiratory distress, and two of them show that BF3 dihydrate may be responsible for kidney toxicity (necrosis of proximal tubular epithelium). This effect was observed in the two Rusch studies (subacute toxicity study and 90-day toxicity study) and is correlated with increase of fluorine amounts in urine and in serum that were not considered as adverse but that are related to kidney effects. The kidney effects in the subchronic toxicity study were not significant as it was observed in only 2 rats of the highest dose group. In the subacute toxicity study all rats of the highest dose group developed necrosis of proximal tubular epithelium. But the histopathological examinations were limited by autolytic changes resulting from the spontaneous deaths of these animals.

key study (Rusch et al., 1986; boron trifluoride dihydrate)
The potential toxicity of boron trifluoride (BF3) was evaluated following repeated inhalation administration for 13 weeks, according to OECD Guideline 413. The substance was tested in a dihydrate form which contained 63.87% of BF3. Aerosols of BF3 dihydrate were administered daily by inhalation to Fischer 344 rats (20 Males and 20 Females), 6 hrs/day, 5 days a week, at the dose-levels of 0, 2, 6, 17 mg/m3 during 90 days. Body weights were recorded pre-test, weekly and at death or prior necropsy. Animals were observed daily for toxicity and pharmacological effects, and twice daily for morbidity and mortality. Whole blood, serum and plasma, and urine were sampled after one month of exposure in 5 animals/sex/dose, during the final week of the exposure period (15 animals/sex/dose) and in the retained animals (5/sex/dose) at the end of the post-exposure period. In addition, fluoride was measured in urine and in blood after 1 and 2 months of exposure and 2 weeks after the final exposure. All animals were examined for gross pathology, and organs were weighted and submitted to histopathology. Tissues from 40 major organs of high-exposure and control groups were examined. In addition, nasal turbinates, kidneys, lungs and liver were examined from all other animals of the study. At 17 mg/m3, one death was attributed to the test substance. No differences were observed between treated and control groups for body weight and haematology. Urine analysis and blood chemistry were affected by treatment. Clinical signs of respiratory irritation were seen, but without abnormal histological findings. An exposure - related depression of total protein concentrations accompanied by an exposure-related depression of globulin concentrations was observed. In urines, an exposure-related depression in calcium amounts and an exposure-related increase in urinary fluoride were noted. The decrease in calcium values was found to be reversible at the end of exposure, contrary to the decrease of urinary fluoride which was partially reversible. Serum fluoride concentrations were markedly increased in all exposure groups (dose-related increase). A recovery was noted after the end of exposure. At necropsy, no differences for organ weight and macroscopic appearance were observed between treated and control groups. At microscopy examination, necrosis of the renal tubular epithelium was seen in the highest dose group and was the apparent cause of a death in one of the animals. Consequently, under the experimental conditions, the No Observed Adverse Effect Level (NOAEL) is 6 mg/m3 and the LOAEL is 17 mg/m3 for effects on kidney. The increase of fluorine amounts in serum and in urine are not considered as adverse since no signs of toxicity were associated and since it was reversible or partially reversible (as the recovery period was only 2 week, a full reversibility was not observed for urinary fluorine); nevertheless they are related to treatment.

supporting study (Rusch et al. 1986; boron trifluoride dihydrate)
The potential toxicity of BF3 dihydrate was evaluated following repeated inhalation administration for 2 weeks, according to OECD Guideline 412. BF3 dihydrate was administered once daily by inhalation to aerosols to Fischer 344 rats (5 Males and 5 Females), at the dose-levels of 0, 24, 66 and 180 mg/m3 6 hours a day, for 2 weeks (5 days the first week and only 4 days the second week).
All rats of the highest dose group died prior to the 6th exposure. No mortality occurred in the other dose groups but the animals elicited signs of respiratory distress and irritation. Mean body weight was decreased at 66 mg/m3. Lung weight was increased in all dose groups. The histopathological findings revealed a necrosis and pyknosis of the proximal tubular epithelium in the kidneys of the high exposure group rats. Nevertheless, the histopathological examinations were limited by autolytic changes resulting from the spontaneous deaths of these animals.
The NOAEL for systemic effects was 66 mg/m3 (tubular necrosis of the kidney). No NOAEL for respiratory distress was determined since it was observed at all dose levels tested.

supporting study (Torkelson et al. 1961; boron trifluoride)
The Torkelson study is a 6 -months toxicity study where rats were exposed to about 2.8 mg/m3, 8.2 mg/m3 or 11.9 mg/m3 of BF3 (gas). The major observed effect was respiratory irritation. Toxicity also involved pneumotitis and dental fluorosis. This study was questionable because of methodological deficiencies, e.g. BF3 was directly instilled into the exposure chambers in order to avoid formation of aerosols of BF3-hydrates. Air humidity was kept down to 30 % which is unusually low. Even the glass was corroded by this rather artificial procedure.
The Rusch study (see key study) appears to be more appropriate and relevant, regarding both experimental generation of BF3 or BF3 dihydrate (BF3 dihydrate aerosols were formed and administered in the Rusch study into an atmosphere with 60 % humidity) and general experimental study design. Nevertheless, respiratory irritation observations are coherent with those of Rusch publications.

Justification for classification or non-classification

Based on the information available for boron trifluoride dihydrate, the test substance is classified as follows: STOT Rep. Exp. 1 (H372) according to Regulation (EC) No. 1272/2008; T, R48/23 according to Directive 67/548/EEC.