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

Endpoint summary

Description of key information

All the inhalation studies conducted with BF3 (gas) or BF3 dihydrate caused signs of respiratory distress. This effect was already seen in the acute toxicity tests. Furthermore, necrosis of the proximal tubuli was 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: ad libitum (Purina 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: 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. These 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: 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  intercompared, exposure groups to 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 F max 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%). One male from the high-exposure group had an elevated blood urea nitrogen. Serum fluoride concentration was 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 (this is the rat  which had an 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, boron trifluoride dihydrate and acetonitrile, which is considered acceptable in accordance with REACH Annex XI, section 1.5, as discussed in IUCLID chapter 7.1.

For these substances only repeated inhalation studies are available.

Boron trifluoride, boron trifluoride dihydrate

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.

Other secondary sources stated signs of respiratory distress as major findings among different species (Kasparov et al., Stokinger).

 

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.

 

 

Acetonitrile

Supporting study (NTP_1996, acetonitrile)

In a 13-week study, the read across substance (acetonitrile) was tested in F344/N rats. Groups of 10 male and 10 female rats were exposed to 0, 100, 200, 400, 800, or 1600 ppm (equivalent to 0, 168, 335, 670, 1340, or 2681 mg/m3) acetonitrile by inhalation for 6 hours per day, 5 days per week for 13 weeks. Six male and three female rats that received 1600 ppm and one male that received 800 ppm died during the study. At exposure concentrations up to and including 800 ppm, the final mean body weights and body weight gains were generally similar to those of the controls. At 1600 ppm, body weight gain was lower and the final mean body weights of both males and females were significantly lower than those of the controls. Hypoactivity and ruffled fur were observed during the first week of the study in males receiving 800 ppm and males and females receiving 1600 ppm. Additional clinical findings in 1600 ppm males that died during week 1 were ataxia, abnormal posture, and clonic convulsions. Clinical pathology findings included nonresponsive, normocytic, normochromic anemia in 1600 ppm males and females and in 800 ppm females, and decreased triiodothyronine (T3) concentrations in 1600 ppm females. Absolute and relative thymus weights were significantly lower than those of the controls in the 800 and 1600 ppm males and females. Females exposed to 1600 ppm had significantly greater absolute and relative heart, kidney, and liver weights than those of the controls. There were no clear exposure-related histopathologic effects, although pulmonary congestion and edema and hemorrhage in the lung and brain were seen in some rats that died early. These lesions are consistent with cyanide-induced anoxia. Several male and female rats exposed to 1600 ppm and one male exposed to 800 ppm died. The deaths occurred primarily during the first week of exposure, suggesting either adaptation of the remaining animals to continuing exposure or a range of susceptibility to acetonitrile-induced lethality. Body weight gains were not affected at exposure concentrations below 1600 ppm, nor were there significant exposure-related clinical findings. Rats that died during the study showed a spectrum of lesions consistent with previous descriptions of acetonitrile-induced toxicity, in addition to lesions typically encountered in early death animals in other NTP studies.

In a 13-week study, the read across substance (acetonitrile) was tested in B6C3Fl mice. Groups of 10 male and 10 female mice were exposed to 0, 100, 200, 400, 800, or 1600 ppm (equivalent to 0, 168, 335, 670, 1340, or 2681 mg/m3) acetonitrile by inhalation for 6 hours per day, 5 days per week for 13 weeks. All mice exposed to 1600 ppm died during the first 3 weeks of the study. In addition, one 400 ppm female and one male and four females from the 800 ppm groups also died before the end of the study. Body weight gains were similar to those of controls for all surviving groups of mice except the 800 ppm males, for which the final mean body weight was slightly lower than that of the controls. Clinical findings observed during the first week in 800 and 1600 ppm mice were hypoactivity and a hunched, rigid posture. In males that received 200 ppm and above, absolute liver weights were greater than that of the controls and relative liver weights were greater in all exposed groups. In 800 ppm females, the absolute liver weight was greater than that of the controls and relative liver weights of females that received 400 ppm and above were greater than that of the controls. Lesions clearly associated with acetonitrile exposure were observed in the stomach, predominantly the fore-stomach, of males that received 400 ppm and above and of females that received 200 ppm and above. Histologically, these focal or multifocal pale to dark raised lesions consisted of areas of focal epithelial hyperplasia and ulceration, sometimes associated with hemosiderin deposition. An increased incidence of cytoplasmic vacuolation occurred in the liver of males and females exposed to 400 or 800 ppm. A lack of fatty degenerative change was observed in the X-zone of the adrenal cortex of 800 and 1600 ppm female mice.

Mice appeared to be more susceptible to acetonitrile-induced mortality than rats. 100% mortality was observed at 1600 ppm in the 13-week mouse study, and mortality in females was observed at doses down to the 400 ppm. As with the rats, body weight gains of survivors were not markedly affected and specific clinical findings were not noted. In contrast to the rats, lesions other than lymphoid depletion were observed in mice, occurring primarily among those mice surviving to the end of the study. These lesions were largely absent in mice dying during the first 3 weeks. In mice, acetonitrile-related toxicity was observed in the adrenal gland, the liver, and the fore stomach. The most significant lesions were hyperplasia with occasional inflammation and ulceration in the fore- stomach. The character of the lesion was similar to fore-stomach lesions occasionally seen in mice in other NTP inhalation studies, suggesting that the effect may not be specifically related to acetonitrile exposure but rather to some other factor associated with the conditions of exposure. However, gastric erosions have been observed with cyanide intoxication, as noted above, and may represent a true effect of acetonitrile exposure.

Justification for classification or non-classification

Classification for the complex of boron trifluoride and acetonitrile is proposed based on the data with boron trifluoride dihydrate  in case of repeated exposure. 

Dangerous Substance Directive (67/548/EEC)
Based on the available data the test item is considered to be classified as toxic (T, R48/23: Toxic: danger of serious damage to health by prolonged exposure through inhalation) under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EC.

Classification, Labeling, and Packaging Regulation (EC) No 1272/2008
Based on the available data the test substance is considered to be classified for as STOT RE 1 (H372: Causes damage to organs through prolonged or repeated exposure (kidney)) under Regulation (EC) No. 1272/2008, as amended for the sixth time in Regulation (EC) No 605/2014.