Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.875 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Local effects

Long term exposure
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.125 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Dose descriptor starting point:
NOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Local effects

Long term exposure
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Additional information - workers

General approach to meeting data requirements / read-across

The toxicological data available for the hexafluorosilicic acid are limited. The substance is listed on Annex I of Directive 67/548/EEC (19thATP) and classified as ‘Corrosive’ (R34) ‘Causes burns’. Waivers are therefore appropriate for a number of toxicological data requirements, for reasons of animal welfare; as detailed in the REACH guidance, animal studies using corrosive test substances should be avoided.

 

Data for sodium hexafluorosilicate

 

Limited data are available for hexafluorosilicic acid; limited data are also available for the closely related salt, sodium hexafluorosilicate. It can be predicted that (with the exception of local effects due to the corrosivity of hexafluorosilicic acid), the toxicity of these two substances will be equivalent and will be due to the hexafluorosilicate ion.

 

Data for hydrogen fluoride and sodium fluoride

 

In aqueous solution (i.e. under physiological conditions following administration to an experimental animal or in a test systemin vitro), hexafluorosilicic acid dissociates to for the hydrogen (hydronium) and hexafluorosilicate ions. At physiological pH and at all concentrations likely to be testedin vivoorin vitro, the hexafluorosilicate ion will be essentially totally hydrolysed to form silicate and fluoride ions. It is predicted that inorganic silicates are of comparatively low toxicity and that the toxicity of hexafluorosilicate compounds (with the exception of any site of contact effects) is therefore due to fluoride. This position is supported by data showing the hydrolysis of hexafluorosilicate but also by a number of comparative studies which demonstrate the comparable absorption and retention of fluoride following the administration of soluble fluoride salts (such as sodium fluoride) and also toxicity typical of fluorides following the administration of hexafluorosilicates. It is notable that hexafluorosilicic acid is the substance most widely used to fluoridate drinking water supplies as it undergoes essentially total hydrolysis to fluoride under aqueous conditions.

 

In summary, therefore, the local effects of hexafluorosilicic acid are known and will be limited to corrosion/irritation at the site of contact (i.e. the skin or respiratory tract in workers). The systemic toxic effects of hexafluorosilicic acid can be predicted by read-across from sodium hexafluorosilicate (or other hexafluorosilicates) or by read-across from water soluble simple fluorides such as hydrogen fluoride (which is similarly corrosive) or sodium fluoride. The toxicological dataset is adequate to fill all relevant data requirements, without the need for the additional testing of a corrosive substance; this approach is fully justified, both on scientific grounds and for reasons of animal welfare.

 

Toxicokinetics

 

The available data show that, following intentional or accidental exposure of animals to hexafluorosilicic acid and other water-soluble hexafluorosilicates, fluoride levels in the blood and excreta demonstrate the bioavailability of fluoride. A study in rats investigating the comparative retention of fluoride when administered as sodium fluoride, fluorosilicic acid, or sodium fluorosilicate did not find significant differences in the proportion of retained fluoride (~64-68%). Fluoride administered either as sodium fluoride or sodium hexafluorosilicate caused the same degree of acute and chronic toxicity in rats and no difference in the amount of fluoride retained in the bones and teeth. No data are available for dermal absorption, however significant absorption of hexafluorosilic acid is not predicted under normal conditions of exposure, the absorption may be increased in accidental exposures where the integrity of the skin is compromised (burns).

Acute toxicity

No reliable data are available for hexafluorosilicic acid, the NTP review reports an acute oral LD50 in the rat of 430 mg/kg bw; however the primary source of this data has not been identified and therefore its reliability cannot been assessed. Waivers are appropriate for acute toxicity by the oral, dermal and inhalation routes due to the classification of the substance as corrosive.

Irritation / corrosion

The substance is listed on Annex I of Directive 67/548/EEC (19thATP) and classified as ‘Corrosive’ (R34) ‘Causes burns’. No further data are required. The results of a non-standard histological investigation in the skin of rats, guinea-pigs and pigs also indicate a corrosive effect which may be delayed and is more marked in damaged skin. Human experience additionally indicates that the substance is likely to be corrosive.

Sensitisation

No data are available. A waiver is appropriate for this data requirement as the substance is classified as corrosive; the local dermal effects of the substance will therefore be dominated by corrosion/irritation and sensitisation is considered to be unlikely. There are no human data from occupational or accidental exposure which indicate either skin or respiratory sensitisation (occupational asthma)

.

Repeated dose toxicity

No reliable data are available for hexafluorosilic acid or sodium hexafluorosilicate. Data from non-standard investigative studies show that the absorption and retention of fluoride following the administration of sodium fluoride, sodium hexafluorosilicate and fluorosilicic acid is comparable and that the repeated dose toxicity of sodium fluoride and sodium hexafluorosilicate is also comparable. This data requirement is therefore addressed by read-across from studies performed with sodium fluoride.

Genotoxicity

No evidence of mutagenicity was seen in a guideline-comparable Ames test performed with hexafluorosilic acid. No evidence of mutagenicity is reported in two Ames tests performed with sodium hexafluorosilicate; a negative Rec assay is also reported. In studiesin vivo, no evidence of genotoxicity is reported in a Drosophila assay or in a mouse bone marrow micronucleus assay. There is therefore no indication that hexafluorosilicate is genotoxicin vitroorin vivo. Although the data set for hexafluorosilicic acid/hexafluorosilicate are technically incomplete according to a strict interpretation of the REACH data requirements, the dataset for fluoride is extensive and has been reviewed recently at EU level in the Risk Assessment Report for hydrogen fluoride. The Risk Assessment Report concluded that, the available data for hydrogen fluoride and sodium fluoride and concludes that fluoride does not interact directly with DNA and is not genotoxicin vivowhen administered via an appropriate route (i.e. by oral or inhalation exposure).  It is therefore concluded that hexafluorosilic acid is not genotoxic.

Carcinogenicity

No data are available for hexafluorosilic acid and none are required in the absence of any evidence of genotoxicity or relevant indications from repeated dose toxicity studies. However data are available for fluoride in the form of sodium fluoride. The EU Risk Assessment Report for hydrogen fluoride has reviewed all of the available data on the mutagenicity and carcinogenicity of hydrogen fluoride and sodium fluoride and concludes that the data are sufficient to suggest that fluoride is not carcinogenic in animals.  It is therefore concluded that hexafluorosilicic acid is also not carcinogenic.

Toxicity to reproduction

No data are available for hexafluorosilic acid. The available data on the reproductive and developmental toxicity of fluoride (in the form of sodium fluoride) has been recently reviewed in the EU Risk Assessment Report on hydrogen fluoride. Although a number of published literature studies indicate that fluoride has adverse effects on fertility and normal foetal development, similar effects were not demonstrated in a comprehensive set of guideline-comparable studies performed by the US FDA. These studies also controlled for fluoride intake from other sources (diet, drinking water) and were therefore considered to be more reliable. The EU Risk Assessment Report concludes that there is no convincing evidence for the reproductive or developmental toxicity of fluoride even at dose levels causing parental toxicity. It is noted that the NOAELs in the reliable FDA studies are higher than the NOAELs for repeated dose toxicity and are therefore sufficiently protective.

Observations in humans

In a report of suicidal ingestion of sodium hexafluorosilicate, the signs and symptoms of toxicity were consistent with fluoride poisoning and responded to treatment with calcium carbonate and calcium gluconate. Reports of accidental occupational exposure to hexafluorosilic acid note severe irritation/corrosivity to the eyes, skin and respiratory tract. The symptoms of inhalation include burning of the eyes and numbness around the lips; symptoms do not necessarily occur immediately; they can appear 24 hours after exposure. The symptoms experienced by a residential population exposed by inhalation as a consequence of an accidental spillage are consistent with the known irritant/corrosive properties of hexafluorosilicic acid.  It is noted that chronic exposure to sodium hexafluorosilicate dust at levels above the eight-hour TWA is reported to result in severe calcification of the ribs, pelvis, and spinal column ligaments; effects on the enzyme system; pulmonary fibrosis; stiffness; irritation of the eyes, skin, and mucous membranes; weight loss; anorexia; anaemia; cachexia; wasting; and dental effects DNEL derivation

The critical effect of systemic fluoride exposure is skeletal fluorosis; epidemiology studies with the read-across substance HF show no effects following chronic exposure to 0.48 mg/m3 total fluoride (gaseous and particulate). Assuming an 8-hour working day and a breathing rate of 1.25 m3/h, this level of exposure is equivalent to 5 mg/day, or (assuming 70 kg mean bodyweight) 0.072 mg/kg bw/d HF (0.069 mg/kg bw/d fluoride).

The EU RAR for HF concludes that fluoride is not genotoxic and that there is no concern regarding fluoride and carcinogenicity. No effects on reproduction were seen in the NTP 2-generation study with sodium fluoride at the highest dose level, equivalent to 10 mg/kg bw/d fluoride. There is no evidence for the developmental toxicity of sodium fluoride even at the maternally toxic levels of 1.23-14 mg/kg bw/d fluoride. There are therefore no additional findings of concern relevant to the derivation of a DNEL for systemic effects.

The SCOEL have recommended (1998) IOEL values of 1.5 mg/m3 (8-hour TWA) and 2.5 mg/m3 (15-minute STEL) for HF.  They concluded that the 8-hour TWA was sufficient to protect against systemic effects (fluorosis) and that the STEL value was adequate to limit peaks of exposure which could result in irritation. Based upon the study of Largent and Columbus (1960), conducted in volunteers exposed for 6 h/d for 10-50d, a STEL (15 mins) of 3 ppm (2.5 mg/m3) was proposed for hydrogen fluoride to limit peaks in exposure which could result in irritation.

Following the same approach for hexafluorosilicic acid, on the basis that local irritant effects will be caused by the generation of HF and systemic toxicity by the liberation of fluoride; correcting for F-content results in short-trem and long-term DNEL values of 3.125 and 1.875 mg/m3, respectively.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.04 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.04 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.56 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.56 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Dose descriptor starting point:
NOAEC

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Local effects

Long term exposure
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.01 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.01 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Modified dose descriptor starting point:
NOAEL

General Population - Hazard for the eyes

Additional information - General Population

DNEL values for the general public are of limited relevance, as exposure to HFS acid is not predicted. The substance will react to liberate hydrogen fluoride, which in turn will react rapidly in the environment to form fluoride and hydronium ions and will further interact with other ionic species naturally present in the environment. Exposure to fluoride may occur following the inhalation of air, however this is likely to be negligible. The deposition of HF onto soil or vegetation may also contribute to the total fluoride intake of the general public, however the contriubution of HFS acid (from industrial sources) to the total fluoride intake is very small in comparison to the contribution of fluoride from natural sources.

DNEL for systemic effects

The critical systemic effect for HFS acid exposure is skeletal fluorosis. The SCOEL have recommended an IOEL value of 1.5 ppm (1.8 mg/m3) to protect against the systemic effects of fluoride exposure in workers. Dermal exposure to HFS acid of the general public is not predicted and, in any case, must be minimised by the use of protective equipment. Dermal absoprtion is not likely except in cases of exposure where the integrity of the skin is compromised (i.e. burns).

An inhalation DNEL for the general public can be derived by the application of an additional assessment factor of 2 to take into account potential additional intra-species variation and an additional factor of 2 to take into account relative breathing rates and the duration of exposure. This results in a DNEL of 0.56 mg/m3 (F-). However the potential fluoride exposure resulting from this DNEL is equivalent to 9 mg/day, which exceeds the upper tolerable daily intake of 7 mg fluoride (EFSA, 2008). An alternative approach to deriving a systemic DNEL would be to allow inhalation exposure to account for 10% of the estimated total daily fluoride intake of 6 mg/day. On this basis, an inhalation DNEL of 0.04 mg/m3 can be derived and is considered to be adequately protective. On the same basis (i.e. allowing for fluoride intake to acccount for 10% of background), an oral DNEL of 0.01 mg/kg bw/d can be derived (assuming bodyweight of 60 kg).

The same values are proposed for short-term and long-term exposure.

DNEL for local effects

The critical local effect for short-term and long-term dermal exposure is irritation / corrosion, however this cannot be quantified and therefore a DNEL is not derived. Dermal exposure to HFS acid of the general public is not predicted and, in any case, must be minimised by the use of protective equipment.

The critical local effect of inhalation exposure to HFS acid is respiratory tract irritation. The EU IOEL value for HF of 2.5 mg/m3 F- (3 ppm) was derived based on the results of the volunteer study of Largent & Columbus (1960) to limit peaks in exposure which could result in irritation. The application of an additional assessment factor of 2 to take into account potential additional intra-species variation in the exposed general population is considered to be appropriate. This approach results in a DNEL (short-term, local, inhalation) of 1.5 ppm (1.25 mg/m3 as F; 1.56 mg/m3 HFS acid). The study used for the derivation of the short-term local inhalation DNEL was of sufficient duration (10 -50 days) to cover longer-term exposure, particularly when combined with the addtional volunteer stuides which do not indicate any potential for irrititaion at lower exposure levels with increasing exposure duration. The inhalation DNEL (long-term, local) is therefore set at the same level as the short-term value.