Hexafluorosilicic acid

Endpoint summary

Description of key information

No data are available for hexafluorosilic acid or sodium hexafluorosilicate. Comprehensive repeated dose oral toxicity data are available for sodium fluoride (NaF) by oral drinking water administration and for hydrogen fluoride (HF) by inhalation; read-across is therefore proposed.

Chronic (6-month) oral exposure of NaF by drinking water to rats and mice resulted in a ‘target’ NOAEL of at least 4.56 mg/kg bw and ‘target’ LOAEL of at least 3.42 mg/kg bw, respectively. Systemic effects were increased fluoride content of plasma, bone and teeth leading to dental fluorosis in rats at higher dose levels, whereas in mice skeletal effects were seen from the lowest dose level in males.

Subchronic (3-month) inhalation of HF in rats showed an overall NOAEL in male and female rats of 0.72 mg/m³ (actual HF concentration) for a 6 hours per 5 days per week for 91 days exposure regimen. This value corresponds to a corrected ‘target’ NOAEL of 0.18 mg/kg bw, which is considered to be very worst case source value the target substance HFS acid does not deposit deep in the lungs (see toxicokinetics). At higher concentrations death, tissue irritation, dental malformations, haematological and biological changes and changes in several organ weights were observed.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

See attached read-across justification

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

read-across source

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

not examined

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY

No deaths occurred. From Week 6, chalky-white teeth with an unusual wear pattern were observed in rats at the high dose level. During the latter stages of the study, teeth were trimmed due to their unusual length; chipping was also observed.

BODY WEIGHT AND WEIGHT GAIN

Bodyweights and food consumption were lower at 300 ppm in both sexes


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)

Water consumption was slightly reduced at 300 ppm.


GROSS PATHOLOGY

Thickening of the gastric mucosa at 100 and 300 ppm.

HISTOPATHOLOGY

The principal effects were observed on the incisor teeth (300 ppm males) and stomach (both sexes at 100 and 300 ppm). In 300 ppm males, degeneration of the enamel organ was apparent. Gastric effects were characterised by a diffuse hyperplasia of the glandular mucosa .


OTHER FINDINGS

Dose descriptor:

NOEL

Effect level:

30 ppm

Sex:

male

Basis for effect level:

other: Gastric pathology

Dose descriptor:

NOEL

Effect level:

30 ppm

Sex:

female

Basis for effect level:

other: Gastric pathology

Dose descriptor:

NOAEL

Effect level:

100 ppm

Sex:

male

Basis for effect level:

other: Reduced bodyweight, food and water consumption; dental fluorosis

Dose descriptor:

NOAEL

Effect level:

100 ppm

Sex:

female

Basis for effect level:

other: Reduced bodyweight, food and water consumption; dental fluorosis

Critical effects observed:

not specified

Dose (ppm)	Survival	Mean Body Weight			Final Weight relative to control (%)
		Initial	Final	Change
Male
Control	10/10	78 ±7	444 ±7	366 ±8	100
Control	10/10	78 ±7	450 ±7	372 ±10	101
Control	10/10	80 ±7	420 ±7*	339 ±8*	94
10	10/10	76 ±7	425 ±9	349 ±7	96
30	10/10	83 ±7	437 ±7	354 ±10	98
100	10/10	76 ±6	433 ±7	357 ±5	97
300	10/10	81 ±7	371 ±10**	290 ±8**	83
Female
Control	10/10	72 ±6	236 ±7	163 ±8	100
Control	10/10	67 ±6	234 ±4	167 ±6	99
10	10/10	75 ±7	232 ±3	156 ±6	98
30	10/10	69 ±7	234 ±6	166 ±7	99
100	10/10	69 ±7	235 ±4	166 ±8	100
300	10/10	70 ±7	212 ±3**	141 ±6	90

*Significantly different (P≤0.05) from the control group by Dunn’s or Shirley’s test

**P<0.01

Conclusions:

Read-across substance Sodium fluoride: There were no deaths throughout these studies. The only observed effects were signs of dental fluorosis and thickening of the mucosa and ulcer formation in the glandular stomach at 100 and 300 ppm.

Executive summary:

Read-across substance sodium fluoride was shown to have an effect on the teeth and stomach of rats in this study. There was no mortality; bodyweights, food consumption and water consumption were reduced at the highest dose level of 300 ppm. Signs of dental fluorosis were apparent in all animals at 300 ppm and microscopically in males at 300 ppm. Local irritant effects on the gastric mucosa (hyperplasia and ulceration) were noted at 100 ppm and 300 ppm, however this local effect is considered likely to be a consequence of the method of administration and is not relevant to the human risk assessment.

.

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

See attached read-across justification

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

read-across source

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY

Deaths occurred at 600 ppm (4 males, 9 females) and at 300 ppm (1 male). Signs of toxiicity (weakness, thin appearance, hunched posture) were seen at 600 ppm. Mice at 100, 200m 300 and 600 ppm had chalky white teeth; the lower incisors were more affected and were also chipped at higher dose levels.

BODY WEIGHT AND WEIGHT GAIN

Reduced weight gain was seen at 200, 300 and 600 ppm; food consumption was reduced in males at 600 ppm. Water consumption was unaffected by treatment.

GROSS PATHOLOGY

None

HISTOPATHOLOGY

Treatment-related findings were noted in the kidney, liver, testes and myocardium of decedents. Acute nephrosis was characterised by extensive multifocal degeneration and tubular necrosis and was diagnosed as the cause of death in these animals. Multifocal myocardial degeneration was also seen in two 600 ppm females. Liver changes consisted of scattered heptocellular hypertrophy and megalocytosis. The effects on the testes (degeneration/necrosis of the seminiferous tunules) were not considered to be directly related to treatment, but occur frequently in moribund mice. Effects were also noted on teh femur and (to a lesser extent) the tibia of mice at 50 ppm and greater. Changes are considered to be indicative of altered rates of bone deposition and remodelling. Effects on the teeth were seen at 300 and 600 ppm.


OTHER FINDINGS

The fluoride content of plasma, bone and urine increased with dose level.

Dose descriptor:

NOEL

Effect level:

< 50 ppm

Based on:

other: sodium fluoride

Sex:

male

Basis for effect level:

other: Effects on bone

Dose descriptor:

LOEL

Effect level:

50 ppm

Based on:

other: sodium fluoride

Sex:

male

Basis for effect level:

other: Effects on bone

Dose descriptor:

NOEL

Effect level:

50 ppm

Based on:

other: sodium fluoride

Sex:

female

Basis for effect level:

other: Effects on bone

Critical effects observed:

not specified

Dose (ppm)	Survival	Mean Body Weight			Final Weight relative to control (%)
		Initial	Final	Change
Male
Control^a	9/9	16.9±0.4	40.2±1.0	23.3±1.1	100
Control^b	10/10	18.6±0.4*	41.6±0.6	23.0±0.7	103
Control^c	11/11	17.8±0.4	39.2±1.0	21.4±1.0	97
10	9/9	17.3±0.5	43.1±1.5	25.8±1.8	107
50	10/10	18.0±0.6	41.1±1.1	23.1±1.3	102
100	10/10	19.2±0.8	41.5±1.1	22.3±1.3	103
200	10/10	17.9±0.7	36.5±1.2	18.6±1.4*	91
300	7/8	18.8±0.7	38.1±1.1	19.0±1.4*	95
600	5/9	17.4±0.4	32.0±1.6**	14.8±1.9**	80
Female
Control^a	11/11	16.9±0.6	30.2±1.4	13.3±1.6	100
Control^b	10/10	18.6±0.4	31.5±1.0	12.9±1.1	104
Control^c	9/9	16.6±0.2	28.7±0.9	12.1±0.8	95
10	11/11	17.1±0.4	29.6±1.1	12.5±1.1	98
50	10/10	16.4±0.3	32.2±1.1	15.8±1.2	107
100	10/10	17.2±0.4	30.6±1.5	13.4±1.4	101
200	10/10	17.2±0.4	25.3±0.6**	8.1±0.7*	84
300	12/12	16.9±0.3	26.2±0.8*	9.3±0.7*	87
600	2/11	16.6±0.4	24.5±1.5	9.0±1.0	81

*Significantly different (P≤0.05) from the control group by Dunn’s or Shirley’s test

**P<0.01

^a         Control group receiving semisynthetic, low fluoride diet and deionised water.

^b      Control group receiving semisynthetic, low fluoride diet and sodium chloride supplemented deionised water

^c      Control group receiving standard NIH-07 diet and deionised water.

Organs and Diagnoses	300 ppm	600 ppm
Male Animals initially in study Early deaths   Kidney Nephrosis, multifocal   Liver Megalocytosis, multifocal Syncytial alteration, multifocal   Myocardium Mineralization, multifocal   Testis Necrosis Tubule, degeneration, multifocal Tubule, multinucleated giant cells, multifocal   Female   Animals initially in study Early deaths   Kidney Nephrosis, multifocal   Liver Megalocytosis, multifocal Syncytial alteration, multifocal   Myocardium Degeneration, multifocal Mineralization, multifocal	8 1     1     1 1     1     1   1       12 0     0     0 0     0 0	9 4     2     4 4     4     3 2 1       11 9     2     7 7     2 4

Conclusions:

Skeletal effects of fluoride were seen at all dose levels in this studywith read-across substance sodium fluoride.

Executive summary:

In the 6 month studies in mice, 4/9 males and 9/11 females receiving 600 ppm read-across substance sodium fluoride and 1/8 male given water containing 600 ppm died.

The fluoride content of urine and bone increased with the concentration of sodium fluoride in the drinking water in both sexes of mice. Bone fluoride concentration were as high as 14.8 µg/mg of ashed bone in male mice receiving 600 ppm sodium fluoride in water. The bone fluoride content found in mice was somewhat greater than that found in rats given comparable sodium fluoride content. This maybe due to a greater water intake on a body weight basis by mice than by rats resulting in higher exposures. Plasma fluoride concentrations in mice showed a good dose relationship and appeared increased in groups receiving water concentrations of 50 ppm of sodium fluoride or higher.

Histopathologic findings for mice are consistent with previously recognised toxic effects. The acute nephrosis observed in the kidneys was probably the most likely cause of death. Lesions were also observed on the incisor teeth, femur and tibia of mice.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

3.42 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Quality of whole database:

reliable

System:

musculoskeletal system

Organ:

bone

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

See attached read-across justification

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

read-across source

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Five males and 1 female exposed to 10 ppm were found dead after Day 47: 1 died on Day 48, 2 died on Day 49, and 1 animal was found dead on each of the following days: 63, 78 and 79.

All clinical signs of toxicity were limited to animals in the 10 ppm group. The earliest clinical changes were a red ocular discharge occurring in both sexes on day 15. Roughened coat occurred in females on Day 15 and in males on Day 22. Other abnormalities including alopecia, thin appearance, hunched posture and nasal discharge occurred in both sexes after Day 20 and persisted until the end of the study. Two male rats developed polypnea on Day 50 continuing to Day 71. A wet urogenital region was observed in both sexes after Day 50 of the study. All animals in the lower concentration groups and in the control group were clinically normal throughout the study period.

There were no differences in body weight gain between the controls and the 0.1 and 1.0 ppm groups. Group mean body weight values of male and female rats from the 10 ppm group increased only slightly during the study and at a decreased rate compared to controls. The 10 ppm male and female group mean body weight was significantly lower than controls from Day 8 until study termination. At week 13 the 10 ppm male group mean body weights were 21% lower than controls, whilst 10 ppm females were 6% lower than controls.

There were concentration-dependent minimal to mild increases in mean platelet counts from all groups of treated rats of both sexes. Mean platelet count differed from controls in a statistically significant manner in all HF-exposure groups of females and in the 10 ppm males. There were also minimal increases in group mean white blood cell counts of all HF-exposed groups, but the increase was only significant in the 10 ppm females. The slight increase in mean white cell counts of treated males were mainly due to increase in the numbers of segmented neutrophils, while in some groups of treated females there was also a contribution from increased lymphocyte counts. 10 ppm males and females had slight but statistically significant decrease in group mean erythrocyte counts. Group mean haematocrit and blood haemoglobin concentration were decreased in the 1 and 10 ppm rats. Mean corpuscular volume and mean corpuscular haemoglobin were significantly increased in 10 ppm males. Mean corpuscular volume was significantly increased in 10 ppm females.

Serum glucose concentrations were significantly decreased in all exposed females, and in 10 ppm males. Mean blood urea nitrogen was statistically singicantly increased in the 10 ppm females. Some other changes were seen (occasional decreased in enzymes, and increases in inorganic phosphorous and potassium concentrations) but there was no dose-response relationship so the changes were thought to have no toxicological significance.

There was a significant decrease in absolute kidney, testis, heart, spleen and liver weight values of 10 ppm males. There was a significant decrease in ovary weight in 10 ppm females. There was a significant increase in absolute brain and adrenal weight values in 0.1 ppm females. There was a significant decrease in absolute lung weight in 10 ppm males and females. There were significant increases in organ:body weight ratios for the adrenal gland, lung, heart and testis in the 10 ppm males. There was a significant increase in spleen:body weight ratios in 10 ppm females, and a decrease in ovary:body weight ratios in this group. Brain and kidney: body weight ratios were significantly increased in both male and female 10 ppm rats. Organ:brain weight ratios were significantly decreased in 10 ppm males for the kidneys, heart, spleen, lung and liver. Adrenal: brain weight ratios were significantly increased in 0.1 ppm females, and kidney:brain weight ratios were significantly increased in 10 ppm females. Ovary and lung to body weight ratios were significantly decreased in 10 ppm females.

All gross lesions observed at necropsy were typical of those observed in rats of this age and strain. Malocclusion was noted at the time of necropsy in 9 male and 2 female 10 ppm rats.

There were no lesions identified at histopathology that were considered to be exposure-related. The rats that died early revealed no lesions related to the cause of their deaths; they had a general shrunken appearance of parenchymal cells, and a stress-related lymphocyte depletion of lymphoid tissues. All of these changes were considered typical of those expected to occur in animals lacking adequate food or water over a period of time.

There were no apparent differences in respiratory rates between dose groups or sex in Weeks 1 through 7. Animals of both sexes in the three lower dose levels continued from Week 7 through Week 13 with no apparent changes. The 100 ppm animals displayed a marked decrease in respiration rates from Week 8 to 12, with an unexplained rise to average mean level at Week 13.

Dose descriptor:

NOAEL

Effect level:

0.88 ppm (analytical)

Based on:

other: hydrogen fluoride

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

Critical effects observed:

not specified

On the first day of exposure the test article concentrations were below target, therefore the exposure period was extended for 1 hour.

The overall mean concentration values recorded for the 91 day exposure period were 0, 0.12, 0.88 and 9.21 ppm for the 0, 0.1, 1.0 and 10 ppm concentration levels, respectively.

Chamber uniformity measurements were completed during pre-validation and the first week of animal exposures, and found to be acceptable.

Conclusions:

The NOAEL for read-across substance Hydrogen fluoride can be considered to be 0.88 ppm (analytical), equivalent to 0.72 mg/m³.

Executive summary:

The potential toxicity of read-across substance hydrogen fluoride (HF) gas was determined in Fischer 344 rats. Twenty rats per sex were exposed to HF gas at concentrations of 0 (filtered-air only), 0.1, 1.0 and 10 ppm, for 6 hours/day, 5 days/week for 13 weeks.

Six rats (5 males and 1 female) from the high dose group died during the study. There were marked body weight decreases in rats exposed to 10 ppm, accompanied by some decreases in selected absolute organ weight values. Clinical signs of toxicity were limited to the animals exposed to 10 ppm, and included red ocular discharge and rough coats. Some effects on haematology and clinical chemsitry parameters were detected, but the changes were slight and considered to be of minimal toxicological significance. The authors concluded that dental malocclusions noted at necropsy were likely to be a contributing factor to changes in blood values and body weights.

It was concluded that repeated exposure of rats to 10 ppm HF caused non-specific progressive toxicity, characterised by general malaise and loss of body weight. The authors also mentioned a decreased appetite and decreased food consumption, although there were no data reported to support this. The toxic effects of HF appeared to be more severe in males.

The NOAEL can be considered to be 0.88 ppm (analytical), equivalent to 0.72 mg/m³.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

0.72 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

reliable

System:

musculoskeletal system

Organ:

bone

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose oral toxicity

No studies have been performed with HFS acid, however comprehensive data are available for sodium fluoride as source substance. The repeated dose oral toxicity studies of NaF in rats and mice via drinking water are considered to be relevant to the target substance, with the exception of likely irritant/corrosive effects at high dose levels. The repeated dose oral toxicity will be due to fluoride, therefore read-across from the comprehensive NTP dataset with the soluble salt NaF is considered appropriate.

 

In a supporting 14 -day range-finding study with NaF in the rat, mortality was seen at drinking water concentrations of 400 and 800 ppm. Signs of toxicity (reduced weight gain, reduced water consumption, lethargy and dehydration) were noted in surviving animals in these groups. The NOAEL for this study was 200 ppm in the water.

In a supporting 14-day range-finding study in the mouse, mortality was seen at the highest dose level of 800 ppm; signs of toxicity (reduced weight gain, abnormal gait and posture, reduced water consumption) were also apparent at this dose level. A NOAEL of 400 ppm in the water was determined for this study.

 

In a 6 -month rat study, the effects of exposure to NaF were limited to reduced weight gain, dental fluorosis, thickening and ulceration of the gastric mucosa at the highest dose level of 300 ppm; gastric effects were also seen at 100 ppm. The fluoride content of plasma, bone and teeth increased with dose levels. The NOEL for this study was 30 ppm in the water, however the local effects at 100 ppm are not considered to be relevant for the risk assessment therefore a NOAEL of 100 ppm in the water can be determined for systemic toxicity. Taking into account a daily water requirement of 20-30 mL/rat (Derelanko, The Toxicologist’s Pocket Handbook, Informa, 2008), a NOAEL of 100 ppm (100 mg/L) corresponds with 2-3 mg/rat. Assuming a mean body weight of 250 g/rat, the NOAEL would be 8-12 mg/kg bw. Application of a conversion factor from source to target substance (see read-across justification) leads to ‘target’ NOAEL of at least 8 mg/kg bw x 0.57 = 4.56 mg/kg bw.

In a 6 -month mouse study, mortality attributable to acute nephrosis was seen at the highest dose level of 600 ppm in the water. Skeletal effects (bone deposition and remodelling in femur and tibia) were seen in males at the lowest dose level of 50 ppm in the water. Taking into account a daily water requirement of 3-7 mL/rat (Derelanko, The Toxicologist’s Pocket Handbook, Informa, 2008), a LOAEL of 50 ppm (50 mg/L) corresponds with 0.15-0.35 mg/mouse. Assuming a mean body weight of 25 g/mouse, the LOAEL would be 6-14 mg/kg bw. Application of a conversion factor from source to target substance (see read-across justification) leads to ‘target’ LOAEL of at least 6 mg/kg bw x 0.57 = 3.42 mg/kg bw.

 

Repeated dose dermal toxicity

No studies are available. The effects of dermal exposure will be dominated by local irritation / corrosion. There is no evidence of significant dermal absorption of HFS acid under exposure conditions where the integrity of the skin barrier is maintained. Testing for repeated dose dermal toxicity can therefore be waived on scientific grounds and for reasons of animal welfare.

 

Repeated exposure inhalation toxicity

The effects of repeated inhalation exposure to HFS acid have been adequately characterised; the effects of repeated exposure to fluoride are also well characterised.

Read-across data are available for hydrogen fluoride (HF). In a supporting published study (Sadilova et al, 1974), female rats were exposed to 1 mg/m³ HF 6 hours/day for 1 month. Effects were noted on the teeth, bones and respiratory tract. Two proprietary studies (Placke et al;1990, 1991) were performed in male and female Fischer 344 rats. In the first study (1990), the rats were exposed to HF gas in a total of 10, 6-hour exposures over a 14 -day period at 0 (air-only control), 1, 10, 25, 65 and 100 ppm. Repeated exposure to 65 and 100 ppm was fatal to both male and female rats, whilst 25 ppm was also fatal to female rats. There were marked body weight decreases in animals exposed to 10 ppm or greater, accompanied by some decreases in selected absolute organ weight values (possibly delayed organ development). Lung to body weight values were elevated in surviving rats exposed to the lower and middle concentrations, suggesting there may have been some pulmonary oedema and/or inflammatory infiltration in the lungs of those animals. Rats of both sexes exposed to 25 ppm and above had corneal opacity and/or crusty epidermal lesions of the ear pinna, which was considered to be due to the caustic effect of HF. Red or brown discolouration or discharges around the eyes and nose of rats of both sexes were also seen at 25 ppm and above, and were presumed to be due to irritation of mucosal surfaces of the ocular and/or nasal tissues. The NOAEL for this study was considered to be 1 ppm in the air. In the second study (1991), Fischer 344 rats were exposed to HF gas at concentrations of 0 (filtered-air only), 0.1, 1.0 and 10 ppm, for 6 hours/day, 5 days/week for 13 weeks. Six rats (5 males and 1 female) from the high dose group died during the study. There were marked body weight decreases in rats exposed to 10 ppm, accompanied by some decreases in selected absolute organ weight values. Clinical signs of toxicity were limited to the animals exposed to 10 ppm, and included red ocular discharge and rough coats. Some effects on haematology and clinical chemistry parameters were detected, but the changes were slight and considered to be of minimal toxicological significance. The authors concluded that dental malocclusions noted at necropsy were likely to be a contributing factor to changes in blood values and body weights.

It was concluded that repeated exposure of rats to 10 ppm HF caused non-specific progressive toxicity, characterised by general malaise and loss of body weight. The authors also mentioned a decreased appetite and decreased food consumption, although there were no data reported to support this. The toxic effects of HF appeared to be more severe in males. The NOAEL can be considered to be 0.88 ppm (analytical), equivalent to 0.72 mg/m³. This corresponds to a target NOAEC of 1.26 x 0.72 mg/m³= 0.91 mg/m³.

Taking into account that inhalation was only 6h/day and 5 days/week, and a rat respiratory volume of 290 L/day (ICH Q3D, 2014), the respiratory value corresponds with 0.15 mg/kg bw/day*. Application of a conversion factor from source to target substance (see read-across justification) leads to a NOAEL of 0.15 mg/kg bw x 1.2 = 0.18 mg/kg bw. When compared to the oral LOAEL/NOAEL values, this value is considered to be very worst case as the target substance (HFS acid) does not deposit into the lungs, whereas the source substance (HF) can.

---

* 0.72 mg/m3 * 6 hours/day * 5 days/week= 0.13 mg/m3 = 0.00013 mg/L

            24 hours/day * 7 days

 

  0.00013 mg/L * 290 L/day= 0.15 mg/kg bw/day

             0.250 kg

 

Summary

Effects of repeated fluoride exposure in experimental animals were seen on the teeth, bones, respiratory tract and kidney. Evidence from epidemiological studies in humans also indicate that prolonged exposure to fluoride causes dental and skeletal effects.

Justification for classification or non-classification

According to CLP Regulation Annex VII, column 2 specific rules of adaptation of 18 December 2006, Hexafluorosilicic acid no classification for repeated dose toxicity is warranted. No classification is proposed in the absence of any relevant data; no GHS classification is proposed.