Hydrogen fluoride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 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

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

Summary of toxicology

Toxicokinetics

Hydrogen fluoride is absorbed into the body and will ionise (>99.99%) to form the hydrogen (hydronium) and fluoride ions under physiological conditions. The absorption of inorganic fluoride across mucous membranes is passive and is independent of the fluoride source. Following inhalation exposure to HF, experiments in various species including man have demonstrated that the large majority of inhaled HF does not reach the lungs but is absorbed via the upper respiratory tract mucosa. Plasma fluoride levels are directly related to HF inhalation and peak at between 60-120 hours after the start of exposure. Following dermal exposure to HF, absorption of fluoride is likely to be minimal except in cases where the normal skin structure is compromised as a consequence of the corrosive effects of the substance. The absorption of fluoride following oral administration of HF has not been investigated, but is likely to be rapidly absorbed. Absorbed fluoride is distributed primarily in the blood, 75% in the plasma and 25% associated with erythrocytes. Half of the plasma fluoride may be bound to organic molecules. Fluoride is rapidly distributed and is sequestered in the bones and teeth, where exchange with hydroxyl groups results in incorporation into the bone and tooth structure. Levels of fluoride in bones and teeth are directly correlated with exposure levels. Fluoride is excreted rapidly as a consequence of glomerular filtration, with a plasma half-life of 2-9 hours. The half-life for skeletal fluoride in humans is reported to be 8-20 years.

Acute toxicity

Hydrogen fluoride is listed on Annex I of Directive 67/548/EEC with R26/27/28 classification ('Very toxic by inhalation, in contact with skin and if swallowed'). No data are available for acute oral toxicity.

A number of published literature studies of acute inhalation toxicity of non-standard design are available in a number of species. Rosenholtz et al (1963), reported LC50 values of 4970, 2690, 2040 and 1310 ppm in the rat for exposure durations of 5, 15, 30 and 60 minutes, respectively. Signs of toxicity included ocular and nasal irritation and respiratory distress. Higgins et al (1972) report a 5 -minute LC50 value of 18200 ppm for the rat; deaths are reported to be delayed (24 hours) and were associated with pulmonary oedema. Rosenholtz et al(1963) also report a 5 -minute LC50 value of 4327 ppm for HF in the guinea pig. The results of these studies indicate that HF should be classified as 'Very toxic by inhalation', which is consistent with the current classification of HF. The EU RAR for HF reviews similar data and reports 1 -hour inhalation LC50 values of 280 mg/m3 in the mouse and 817 -1900 mg/m3 in rats. The RAR also notes that inhalation exposure of humans may damage the respiratory tract. A study by Dalbey et al (1998) notes more severe effects of HF inhalation in rats exposed mouth-only compared to those exposed nose-only.

No standard studies of acute dermal toxicity are available. Derelanko et al (1985) investigated the dermal toxicity of diluted hydrofluoric acid in the rabbit and demonstrated local corrosive effects but no systemic toxicity. Cox & Osgood (1994) similarly showed corrosive effects following dermal application of hydrofluoric acid. The EU RAR for HF also notes that dermal contact with liquid or gaseous HF can cause severe dermal lesions and may also result in systemic (cardiac) effects which may be fatal.

Mitsui et al (2007) report an intravenous LD50 in the rat of 17.4 mg/kg bw.

Irritation and corrosivity

HF is classified as Corrosive (R35). In a standard OECD 404 study performed with 5% hydrofluoric acid, Martins (1990) reports corrosive effects. Thyssen (1981) notes no local dermal effects in a study peformed with 0.13% and 1.06% hydrofluoric acid. Wang et al report that 20% of HF was enough to cause skin damage in the rata and might bring about fatal hypocalcemia after a prolonged contact. High concentrations of HF (40%) caused deep tissue necrosis within a short time and resulted in fatal hypocalcemia within 24 hours even in the case of a small area injury. Klauder et al(1955) report no dermal reactions in rabbits resulting from application of 1%, 2% and 4% HF. Transitory blanching occurred at 6%, 8% and 10%. After application of 12%, 15% 18% and 22% crust formation appeared in about 24 hours at site of blanching and disappeared in about one week. Application of 25% and 30% caused blanching followed by redness, later crust formation. These effects were observed from 35% and 40% and in addition, blistering and superficial ulceration. These reactions were more pronounced from 50% concentration and were followed by deep ulceration. The EU RAR for HF also notes that, in humans, dermal contact with HF can cause second and third degree burns which are associated with severe pain and which heal very slowly. Thyssen (1981) also notes no ocular effects with 0.13% hydrofluoric acid and moderate irritation with 1.06% hydrofluoric acid.

Sensitisation

There are no animal data which suggest that HF or fluoride are skin sensitisers; the local effects of HF exposure will be dominated by irritation/corrosion. Similarly there is no evidence of skin sensitisation from occupational exposure; reports of delayed dermal effects in some accidental exposures cases are due to irritancy rather than sensitisation. Similarly there is no evidence of respiratory sensitisation (asthma) from occupational exposure.

Repeated dose toxicity

No oral studies have been performed with HF, however comprehensive data are available for sodium fluoride. The repeated dose oral toxicity of HF and NaF are considered to be essentially identical, with the exception of likely irritant/corrosive effects of HF at high dose levels. The repeated dose oral toxicity of HF will be due to fluoride, therefore read-across from the comprehensive NTP dataset with the soluble salt NaF is appropriate.

In a 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 a 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 is 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, however these local effects are not considered to be relevant for the risk assessment therefore a NOAEL of 100 ppm can be determined. In a 6 -month mouse study, mortality attributable to acute nephrosis was seen at the highest dose level of 600 ppm. Skeletal effects were seen in males at the lowest dose level of 50 ppm. No studies of repeated dose dermal toxicity are available. The effects of dermal exposure to HF will be dominated by local irritation / corrosion. There is no evidence of significant dermal absorption of HF under exposure conditions where the integrity of the skin barrier is maintained, however marked systemic fluoride toxicity is seen where the skin is damaged. In a published inhalation toxicity 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) are summarised in the EU RAR, however the data owner is unknown and therefore there is no access to these studies. The EU RAR summary states over-all NOAEL for repeated inhalatory exposure in male and female rats was identified as 0.72 mg/m³(actual HF concentration) for a 6 hours per 5 days per week for 91 days exposure regimen. 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.

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.

Genetic toxicity

No evidence of mutagenicity was seen in a guideline-compliant GLP Ames test with HF (Herbold, 1987). No evidence of mutagenicity was seen with sodium fluoride in an Ames test (NTP, 1990). No evidence of mutagenicity was seen in a mammalian cell mutation assay (V79/HPRT) with sodium fluoride. This study was performed only in the absence of metabolic activation, however this deviation is not considered to be critical as the test substance is not metabolised. A positive result with sodium fluoride is reported in a mouse lymphoma assay (NTP, 1990). Sister chromatid exchange and chromosomal aberrations are reported in an additional NTP study with sodium fluoride. In vivo, Gerdes (1971) reports a marginally (but not statistically significant) postive response in a study in Drosophila melanogaster; positive effects in Drosophila are also reported by Mohamed et al (1971). The significance of these results is unclear; the EU RAR for HF considers the findings of these two Drosophila studies to be inconclusive. Zeiger et al (1994) report no evidence of clastogenicity, even at dose levels causing severe toxicity, in a well-conducted mouse study performed with sodium fluoride in which chromosomal aberrations and micronucleus formation was assessed. In contrast, a poorly reported inhalation exposure study performed with HF (Voroshilin et al, 1975) reports clastogenicity in the bone marrow of exposed rats but no dominant lethal effect in exposed mice.

The EU RAR concludes that, while the dataset on the genotoxicity of HF is limited, studies with sodium fluoride are also informative as for both substances target tissues will be exposed to fluoride (either free or bound to organic molecules). The EU RAR therefore reviews the available data for NaF and HF and concludes that fluoride does not interact directly with DNA and is not genotoxic when administered via an appropriate route (i.e. by oral or inhalation exposure).

Carcinogenicity

There are no carcinogenicity studies available for HF. The effects of chronic HF exposure will be dominated by local effects at the site of contact (irritation/corrosion), therefore performing studies with HF cannot be supported for scientific reasons and also on animal welfare grounds. Once absorbed into the body, HF will dissociate into its constituent ions and systemic toxicity will be due to fluoride. The analagous behaviour of sodium fluoride (or any other water-soluble fluoride salts) means that read-across from NaF to HF is scientifically justified.

The NTP rat study showed evidence of an effect of sodium fluoride administration on the bones and teeth, consistent with the findings of other studies. There was no effect on survival in this study; bodyweights, food and water consumption, haematological and clinical chemistry parameters and organ weights were unaffected by treatment. Serum, urine and bone fluoride concentrations were increased in all treated groups; the urine calcium concentration was also marginally higher in females at the highest dose level. Osteosclerosis was seen in females at the highest dose level. The incidence of osteosarcoma was increased in males at the intermediate dose level (2%) and the high dose level (4%) but was within the historical range (0 -6%; mean 0.5%). The NTP concluded that the study provides 'equivocal evidence' for carcinogenicity in male rats. An additional carcinogenicity study with NaF in the rat is available (Maurer et al,1990). No evidence of carcinogenicity was seen in this study, at dose levels sufficient to cause toxicity.

The NTP mouse study showed evidence of an effect of sodium fluoride administration on the teeth, consistent with the findings of other studies. There was no effect on survival in this study; bodyweights, food and water consumption, haematological parameters and organ weights were unaffected by treatment. Clinical chemistry revealed elevated ALP activity in females at the highest dose level. Microscopic findings were limited to dentine dysplasia in male mice at 175 ppm. There was no evidence of carcinogencity in either sex. An additional carcinogenicity study with NaF is available (Maurer et al, 1993). A high level of osteosarcomas was seen in all (control and treated) groups in this study, a finding which was attributed to infection with a retrovirus. No conclusion on the carcinogenicity of sodium fluoride can therefore be drawn from this study.

Reproductive toxicity studies

No studies are available for hydrogen fluoride, however the effects of sodium fluoride on fertility have been reported in a number of studies; read-across is considered to be appropriate as the systemic toxicity of HF and NaF wil be due to the effects of fluoride and therefore will be essentially the same.

Adverse effects of sodium fluoride on fertility have been reported in a number of published studies. Araibi et al(1989) report effects on the fertility of male rats administered sodium fluoride in the diet at concentrations of 100 and 200 ppm. Exposure resulted in a reduction in successful matings and reduced litter size; findings were associated with a reduction in seminiferous tubule diameter and a thickened peritubular membrane. The numbers of tubules containing spermatozoa were decreased and serum testosterone levels were also reduced. Chinoy & Sequeira (1989) report alterations in the histoarchitecture of the testes in mice gavaged with sodium fluoride at dose levels of 10 and 20 mg/kg bw/d for 30 days. Findings were characterised by severe disorganisation and denudation of germinal epithelial cells of the seminiferous tubules, absence of sperm from the tubular lumen, reduced in epithelial cell height, nuclear pkynosis, denudation of cells and absence of sperm occurred in the cauda epididymis. The effects seen after 30 days administration were reversible. Chinoyet al(1992) report reduced fertility in male rats administered sodium fluoride by gavage at dose levels of 5 and 10 mg/kg bw for 30 days. Findings were accompanied by reduced sperm count and motility and various biochemical changes in the testes. Messer et al (1973) investigated the reproductive toxicity of sodium fluoride in a two-generation study in which female mice were administered the test material in the drinking water at dose levels of 0, 50, 100 or 200 ppm. A progressive decline in litter production was seen in the control group. All females administered 200 ppm fluoride died over the study period; only a small number of litters were produced at the 100 ppm. It is suggested that a level of 50 ppm sodium fluoride (equivalent to approximately 7.5 mg/kg bw/d fluoride) is required to maintain reproductive capacity in female mice. In a 3 -generation mouse study (Tao & Suttie, 1976), no effects of fluoride on reproduction were seen. The study is of limited value, however the authors suggest that the effects of fluoride seen in the study of Messer et al (1973) was due to the influence of fluoride on teh absorption of iron from a low iron diet. While the results of these studies are consistent, their value and reliability is significantly compromised by the absence of any information on the fluoride levels in diet and/or drinking water. The actual levels of fluoride exposure cannot be accurately assessed.

It is notable that the findings of the published investigative studies of non-standard design contrast with the total absence of reproductive toxicity at comparable dose levels in studies performed by the US FDA. The effects of sodium fluoride administration on spermatogenesis in rats were investigated in a two-generation study (Sprando et al, 1997). In contrast to the previous studies, no effects were observed on reproductive organ weights, sperm parameters or biochemical parameters at dose levels of up to 250 ppm (drinking water). Additional deatiled investigations by the same authors did not reveal any effects on spermatogenesis in F1 males (Sprando et al, 1998). No effects on reproduction were seen at the highest dose level of 250 ppm in a guideline-comparable two-generation rat study (Collins et al, 2001). In a further FDA study designed primarily to assess the potential effects of fluoride on spermatogenesis (as indiceted in various published studies), Sprando et al (1996) demonstrated that injection of sodium fluoride into the rat testis was without effect on spermatogenesis.

In contrast to the studies which report effects of fluoride on male fertility and spermatogenesis, no effects were observed in the FDA studies following extensive investigation. The two-generation FDA study is of standard design and is comprehensively reported, and it is notable in these studies that the contribution of diet and drinking water to the total fluoride intake was assessed. The EU RAR for HF also considers the data available for the reproductive toxicity of NaF and concludes that the FDA studies are key, for reasons of design, reporting and control of fluoride levels. The EU RAR concludes that the NOAEL for reproductive toxicity is 250 ppm NaF, which corresponds to approximately 10 mg/kg bw/d fluoride. The absence of any apparent effects on the reproductive organs in chronic toxicity and carcinogenicity studies is also notable.

Developmental toxicity studies

In a rat developmental toxicity study (NTP, 1994; Heindelet al, 1996), maternal toxicity (transiently reduced bodyweight gain) was apparent at the highest dose level of 300 ppm sodium fluoride (in drinking water), equivalent to 13 mg/kg bw/d fluoride. No evidence of developmental toxicity was seen at this dose level. No clear evidence of developmental toxicity was seen in an FDA rat study (Collins et al,1995) at dose levels of up to 250 ppm sodium fluoride in drinking water (equivalent to 12.3 mg/kg bw/d fluoride). Maternal toxicity in this study was limited to reduced food intake at the highest dose level. No evidence of developmental toxicity was seen in a rabbit study (NTP, 1993; Heindelet al, 1996) at dose levels of up to 400 ppm sodium fluoride (equivalent to 14 mg/kg bw/d fluoride from all sources).

Neurotoxicity

In a single published study, sodium fluoride exposure was found to cause sex and dose specific behavioural disruption (as measured by computer pattern recognition in a novel environment), with a common pattern. Males were most sensitive to prenatal day 17 -19 exposure, whereas females were more sensitive to weanling and adult exposures. After fluoride ingestion, the severity of the effect on behaviour increased directly with plasma F levels and F concentrations in specific brain regions (Mullenixet al, 1995).

Observations in humans

A number of case reports of accidental exposure to HF are available. Following dermal exposure, hydrofluoric acid causes skin burns, the nature and severity of which are related to the concentration of the acid. Symptoms following exposure to lower concentrations may be delayed. Systemic fluoride toxicity (which may be severe and is potentially fata) has been reported in cases of dermal exposure resulting in burns; effects are due to hypocalcaemia and subsequent cardiac effects. Local irritation and systemic fluoride toxicity is also reported in cases of accidental inhalation of HF.

Human volunteer studies

Lund et al (1999) report changes in cellular and biochemical parameters of BAL fluid consistent with respiratory irritation in volunteers exposed to HF for one hour at 'intermediate' (0.7 -2.4 mg/m3; mean 1.16 mg/m3) or 'high' (2.5-5.2 mg/m3) concentrations but not at a 'low' concentration (0.6 mg/m3). The results of later study by the same group (Lund et al, 2005) indicate a transient respiratory irritant effect following a 1 -hour inhalation exposure of volunteers to HF at 0.2 -0.5 mg/m3. In studies by Largent (1960, 1961), volunteers were exposed for 6 hours/day; 15-50 days to low concentrations of HF and irritant effects were assessed. No systemic effects were observed. Mild discomfort (slight eye stinging, slight stinging of the facial skin, slight irritation of the nasal mucosa) was reported at concentrations of up to 2 ppm (1.64 mg/m3). At higher concentrations, erythema and desquamation of the superficial epithelium of the facial skin was observed. Symptoms of mild irritation resolved with cessation of exposure, erythema persisted for a short period of time. No effects were reported at the lowest concentration of 1.42 ppm (1.16 mg/m3).

Worker monitoring data

Kono et al (1992) demonstrate that exposure to HF can be monitored by determining serum fluoride concentration. The same group (Kono et al, 1993) show that worker fluoride exposure can be monitored by determining serum, urine and hair levels of fluoride.

Epidemiology studies

Hodge and Smith (1970) report that worker exposure to levels of airborne fluoride greater than 2.5 mg/m³resulted in an increased occurrence of fluoride induced osteosclerosis. In another study, no overt signs of skeletal fluorosis were observed in workers exposed up to 0.48 mg F/m3 (as a combination of 0.2 mg/m3 for gaseous fluoride and 0.28 mg/m3 for fluoride dust) for up to ten years. Blood biochemistry parameters did not indicate any occurence of hepatic or renal effects. Serum calcium but not phosphate was increased in the highest exposure group (Chan-Yeung et al, 1983a). Meng et al (1995) report an increased incidence of SCEs in the peripheral blood lymphocytes of 40 workers at a phosphate fertiliser factory in Northern China. HF and SiF4 were reported to be the 'main' air pollutants, however workers were also exposed to various other pollutants, thereby limiting the value of the study. Freni (1994) reports a 'highly significant association' between birth rate and fluoride exposure based on drinking water levels. However the EU RAR notes that this study was performed at population level and is significantly flawed due to a number of confounding factors which were not taken into account. It was concluded that a causal relationship was not demonstrated

Beneficial effects of fluoride

Numerous studies in the USA and Europe have shown that a baseline level of fluoride consumption from early childhood affords considerable protection against dental caries, without any visible effects on tooth colouration. Fluoride is usually added to drinking water at a level of 1 mg/L. The EU RAR notes that there are indications that fluoride is an essential nutrient which may play a role in dentition and skeletal development.

Local effects: dermal exposure

 

The studies of Largent (1960, 1961) report slight stinging of the eyes and facial skin at HF concentrations causing respiratory irritation, with more marked dermal irritation (erythema and desquamation) apparent only at higher concentrations. The DNEL for local respiratory tract effects is therefore considered to be sufficiently protective for dermal and ocular irritation; separate dermal DNEL values are not derived. Significant dermal absorption of HF is not predicted expect in cases of accidental expousure, where the integrity of the skin barrier has been compromised. PPE and engineering controls should be used to eliminate the potential for direct dermal exposure, due to the corrosive nature of the substance.

 

Systemic effects

 

Data are available from good quality animal studies and also epidemiology studies and are consistent. The studies of Placke et al (1990, 1991) report a NOAEL for systemic effects in rats at 0.72 mg/m3. The epidemiology study of Chan-Yeung et al (1983a) reports no signs of fluorosis in workers exposed for 10 years at an exposure level of 0.48 mg/m3 (total fluoride). The epidemiological data are considered to be most relevant and therefore are a more suitable starting point for the risk characterisation for systemic effects in workers. In addition it is noted that the relevant endpoints of systemic fluoride toxicity are the same in the animal and human volunteer studies, and that rats are generally considered to be less sensitive to skeletal fluorosis due to greater bone remodelling. The NOAEL of 0.48 mg/m3 from the epidemiology study can therefore be used as a starting point for risk characterisation for systemic effects.

However it essential also to consider the fact that fluoride is widely considered to have a benefical effect on human health. This fact, together with the relatively steep dose-response curve for fluoride and the background levels of intake from other sources, may result in the calculation of an unrealistically low systemic DNEL when all assessment factors are applied.

The EU RAR for HF considers the normal background intake of fluoride by adults to be 5.99 mg/day, consisting of 5.64 mg/day from food and drinking water (non-fluoridated areas), 0.05 mg/day from air and 0.3 mg/day from dental products. This level of background intake is equivalent to 0.1 mg/kg bw/d fluoride, assuming a bodyweight of 60 kg.

There is no evidence for any systemic effects of HF following short-term/acute exposures to levels not causing local irritation, therefore the short-term DNEL for local effects is considered to be adequately protective for short-term systemic effects.

Other effects

 

The critical effect of systemic fluoride exposure is skeletal fluorosis; epidemiology studies with 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 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. The use of IOEL values is justified as there is no new scientific information which indicates that the IOEL values do not provide an appropriate level of protection under REACH.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.03 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.03 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:

0.2 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:

1.25 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

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

high 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:

0.01 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

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - General Population

DNEL values for the general public are of limited relevance, as exposure to HF is not predicted. Hydrogen fluoride 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 HF (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 HF 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 HF of the general public is not predicted and, in any case, must be minimised by the use of protective equipment. Dermal absoprtion of HF 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 0.45 mg/m3. 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 0.03 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). A level of 10% of background is somewhat abitrary, however this level chosen as one that would not be expected to add significantly to the overall exposure to fluoride from other sources.

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 HF 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 HF is respiratory tract irritation. The EU IOEL value 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 (representing the potential for greater sensitivity of individuals within the general population cpmpared to workers and consitent with REACH guidance) 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). The study used for the derivation of the short-term local inhalation DNEL was of 10 -50 day duration, therefore an additional factor of 6 is used to cover longer-term exposurs. The inhalation DNEL (long-term, local) is therefore set at 0.25 ppm (0.2 mg/m3).