Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.89 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Modified dose descriptor starting point:
other: IOEL HF
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.15 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Dose descriptor starting point:
other: IOEL HF

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

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 in Table 3 of Annex VI to the CLP Regulation. (in force from 1 March 2018) as "Skin Corr. 1B (H314). 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 tested in 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. Dermal absorption is possible based on physicochemical properties and also supported by the corrosive properties, which will enhance penetration. Taking into account that hydrolysis takes place in humid conditions to hydrogen fluoride, complete dermal absorption cannot be excluded. Absorption by inhalation is not expected, which is also founded by literature data on silicate compounds hydrolysing to hydrogen fluoride, which does not reach the lungs.

 

Acute toxicity

No reliable acute toxicity data have been identified for the substance: no testing has been performed and non is proposed. The substance is classified as H314 – Causes severe skin burns and eye damage (R34) corrosive according to CLP Regulation (No. 1272/2008 of 16 December 2008)Directive 67/548/EEC (19th ATP), therefore acute toxicity will be dominated by local (site of contact) irritant and corrosive effects. Testing of the substance for acute toxicity is not justified on scientific grounds and for reasons of animal welfare and was waived based on GLP Regulation Annex VII, column 2 specific rules of adaptation of 18 December 2006.

 

Irritation / corrosion

Hexafluorosilicic acid is listed Table 3 of Annex VI to the CLP Regulation. (in force from 1 March 2018) as "Skin Corr. 1B (H314) on Annex I of Directive 67/548/EEC with classification as 'Corrosive' (R34) 'Causes burns'. No additional data are available and none are required.

 

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 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 over-all NOAEL for repeated inhalatory exposure in male and female rats as 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 ‘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). No adverse effects were noted at this concentration. At higher concentrations death, tissue irritation, dental malformations, haematological and biological changes and changes in several organ weights were observed.

 

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 studies in 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 genotoxic in vitro or in 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 genotoxic in vivo when 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). This would correspond with a ‘target’ exposure of 1.2 x 0.072 mg/kg bw/d = 0.087 mg/kg bw/day.

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 11.4 mg/kg bw/d fluoride. There is no evidence for the developmental toxicity of sodium fluoride even at the maternally toxic levels of 10.3 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 as F-) and 2.5 mg/m3 (15-minute STEL as F-) for HF (SCOEL/SUM/56 final December 1998). 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 as F-) 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 following values

- Long term (8h): 1.5 mg/m3 as F- corresponds with 1.58 mg/m3 as HF, which leads to a ‘target’ TWA of 1.2 x 1.58 mg/m3 = 1.89 mg/m3

- Short term (15’): 2.5 mg/m3 as F- corresponds with 2.625 mg/m3 as HF, which leads to a ‘target’ STEL of 1.2 x 2.63 mg/m3 = 3.15 mg/m3

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
DNEL related information
Modified dose descriptor starting point:
other: IOEL HF
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:
other: IOEL HF

Local effects

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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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:
0.013 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Modified dose descriptor starting point:
other: EFSA AI fluoride
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.013 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Modified dose descriptor starting point:
other: EFSA AI fluoride

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

DNEL values for the general public are of limited relevance, as exposure to HFS acid is not expected. 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 8-hour TWA of 1.5 mg/m3 and short term STEL (15’) of 2.5 mg/m3, corresponding with a target long term DNEL of 1.89 mg/m3 and target short term DNEL of 3.15 mg/m3 to protect against the systemic effects of fluoride exposure in workers. Dermal exposure to HFS acid of the general public is not expected and, in any case, must be minimised by the use of protective equipment. Dermal absorption 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 (factor 10 instead of factor 5) and an additional factor of 2 to take into account relative breathing rates and the duration of exposure (20 m3/day instead of 10 m3/8h). This results in a target long term DNEL of 0.47 mg/m3 . However the potential fluoride exposure resulting from this DNEL is equivalent to 9.4 mg/day (20 m3 x 0.47 mg/m3), which slightly exceeds the upper tolerable daily intake of 3 mg fluoride (EFSA, 2013), corresponding to target general population DNEL of 1.26 x 3 mg/day = 3.78 mg/day. The latest acceptable intake of fluoride (AI) from all sources (including non-dietary sources) is 0.05 mg/kg body weight per day for both children and adults, including pregnant and lactating women. For adults of 60kg, this would be 3.0 mg/day (as F-). Major dietary fluoride sources are water and water-based beverages or foods reconstituted with fluoridated water, tea, marine fish, and fluoridated salt. The average total dietary fluoride intake of the adult population in the UK was to be 1.2-1.78 mg/day. Taking into account these other sources (including tooth paste), it is recommended to reduce the general population DNELS to 20% of the EFSA AI (0.6 mg/day) , leading to a ‘target‘ AI of 0.1.26 x 0.6 mg/day = 0.76 mg/day.

 

When the target general population AI of 0.76 mg/day is taken as departure point, this corresponds with a target inhalation long term DNEL of 0.76/ 20 m3 = 0.04 mg/m3  and target oral long term DNEL of 0.76 mg/day/ 60 kg = 0.01 mg/kg bw.

 

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 expected 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; 1.58 mg/m3 HFS acid). For the DNEL Locoal effect – long term, the 8-h TWA based value was used:I OEL (SCOEL, 1998): 1.5 mg/m3 (8-hourTWA as F-) ≈ 1.58 mg/m3 HF, leading to a ‘target’ TWA of 1.2 x 1.58 mg/m3= 1.89 mg/m3.Application of an extra intraspecies factor (10/5) of 2 leads to 1.89 mg/m3/2 = 0.95 mg/m3.

 

References:

 

EFSA Scientific opinion on Dietary Reference Values for fluoride. EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA)2, 3 European Food Safety Authority (EFSA), Parma, Italy - EFSA Journal 2013;11(8):3332  - doi:10.2903/j.efsa.2013.3332 Available online: www.efsa.europa.eu/efsajournal © European Food Safety Authority, 2013

 

SCOEL/SUM/56 final, December 1998; Recommendation from Scientific Committee on Occupational Exposure Limits for Fluorine, Hydrogen Fluoride and Inorganic Fluorides (not uranium hexafluoride)

Categories Display