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

Endpoint summary

Description of key information

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

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.

 

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.

 

 

Methanol

Animal data

Oral:

Seven male monkeys received daily doses of 2340 mg/kg bw methanol as 30% aqueous solution by oral gavage for three days. Under the test conditions, this dosage was lethal for all seven animals (Rao et al., 1977).

Inhalation:

In a whole-body inhalation study in monkeys exposed to 0.013, 0.13, and 1.3 mg/L for 21 hours/day, 7 days/week for 7, 19, and 29 months, several general clinical signs as well as degenerative effects in the brain (at 0.13 and 1.3 mg/L), slight peripheral nerve damage (at 0.13 and 1.3 mg/L), very slight degeneration of the optic nerve (concentrations not noted), increased fat granules and slight fibrosis in the liver (all concentrations) as well as Sudan positive granules in the kidney were observed (at 0.13 and 1.3 mg/L). Also, a slight myocardial disorder (at 0.13 and 1.3 mg/L) and localized effects in the trachea and possible slight fibrosis in the lungs (concentrations not noted) were observed. Although the statistical significance of the effects cannot be verified from the limited study report, the effects observed appear to be associated with methanol (NEDO, 1987).

In a short-time experiment, monkeys were exposed up to 20 days for 21 hours per day to methanol vapour. Coma and lethality were observed at concentrations > 9.31 mg/(L*d). In the brain, necrosis of the basal ganglia and cerebral edema were observed at 6.65 mg/(L*d) and at 3.99 mg/(L*d), hyperplasia and fibrosis around myelin sheaths of the basal ganglia as well as a slight to moderate increase in astroglia cells were observed. The optic nerve showed atrophy at > 3.99 mg/(L*d), along with reduction in myelin fibers. In the liver, fibrosis was observed at 6.65 mg/(L*d) and mild fatty degeneration was observed at 3.99 mg/(L*d). In the kidney, partly vacuolated hyaline degeneration was observed at 6.65 mg/(L*d) (NEDO, 1987). The liver and kidney effects were recorded at doses already overtly toxic in humans and, hence, are of low relevance.

In rats exposed to methanol up to 6.65 mg/L for 6 hours per day, five days per week for 28 days, no adverse effects were observed except local nasal irritation and increased relative spleen weights, which were observed only at the middle dose. The estimated blood level of methanol was about 250 mg/L under this condition (Andrews et al., 1987).

In a whole-body inhalation study in mice exposed for 12 months to concentrations of 0.013, 0.13, and 1.3 mg/L for 20 hours/day, slight changes in clinical signs, body and organ weights, and some changes in histopathology were observed, but these effects were considered to be toxicologically irrelevant (NEDO, 1987). In rats exposed in the same manner, slight changes in body weight and organ weights were observed at the highest dose. The NOEC was 0.13 mg/L, the NOAEC was 1.3 mg/L for rats and mice in these studies (NEDO, 1987). Again, these effects are of low relevance in the light of the onset of human toxicity already at lower doses. The species-related differences are very obvious between rodents and primates.

The latter demonstrating a 100-fold greater susceptibility for methanol-related effects due to differences in metabolism of methanol. In rodents methanol is metabolized to carbon dioxide to a great extent, whereas in primates formate accumulation is responsible for the observed effects.

Human data:

In male and female workers exposed to methanol from 0.3 to 7.8 years, the highly exposed workers (4.7 - 7.3 mg/L) more often complained of blurred vision, headache and nasal irritation during or after work. Nobody stated to suffer from photophobia. The examination of the eye fundus failed to reveal retinal changes. Among three workers exposed to about 1.0 to 1.6 mg/L and one worker exposed to 0.12 to 3.6 mg/L, two showed retarded pupil reflex and one exhibited mild mydriasis (Kawai et al., 1991). Other common complaints were forgetfulness and skin sensitivity (IPCS/WHO, 1997).

A health hazard evaluation was conducted by the National Institute for Occupational Safety and Health (NIOSH) to determine if vapours from duplicating fluid (99% methyl alcohol) used in direct-process spirit duplicating machines were causing adverse health effects among teacher aides (Frederick et al., 1984). The teacher aides reported significantly more blurred vision, headache, dizziness, and nausea than the comparison group. Concentrations of airborne methyl alcohol ranged from 0.48 to 4.0 mg/L. Additional studies also showed that headaches were associated with occupations that involve the operation of duplicating machines (NTP, 2003; IPCS/WHO, 1997).

Justification for classification or non-classification

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

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.