Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Additional information - workers

Overview of the toxicity data for calcium fluoride

It can be predicted that the toxicity of the substance calcium fluoride (CaF2) will be due to the contribution of fluoride. The toxicity of fluoride is well known and has been extensively investigated in studies performed with soluble fluoride salts such as sodium fluoride. The only differences in the toxicological profile of calcium fluoride are therefore attributable to differences in the bioavailability of fluoride from this substance of low solubility; however the presence of the calcium ion may also reduce the toxicity of fluoride.

Toxicokinetics

In a study using 12 paired groups of albino rats, the authors administered fluoride in the form of calcium fluoride or cryolite in the drinking water for 14 weeks. Total fluoride intake (from the basal diet and drinking water) amounted to a dose level of approximately 0.75 mg/kg bw/d. Bodyweight gain and food consumption were retarded in both dose groups. Clinical signs were limited to transient haematuria in both groups, and the appearance of dental striations in all animals from Week 8 -10. Analytical derminations at necropsy revealed fluoride retention of approximately 59%, and that the large majority of the fluoride in the body was present in the skeleton (~96%). No differences were apparent between the treated groups. The authors conclude that the effects of fluoride from these two insouble salts are comparable (Lawrenz et al, 1939).

In a review of a number of volunteer studies, the absorption of fluoride from the gastrointestinal tract is reported to be remarkably effective, with nearly complete absorption of sodium and calcium fluoride in solution (96 -97%) and lower absorption from solid calcium fluoride (62%). Approximately half of the absorbed fluoride is excreted and half retained in the skeleton. Evidence suggests that excretion is urinary, with the small proportion of orally administered fluoride excreted in faeces representing the unabsorbed fraction. The excretion of fluoride in sweat may also be significant (Largent, 1960). The dissolution rate of calcium fluoride tablets in vitro and the degree of fluoride absorption in vivo after calcium fluoride and sodium fluoride tablet intake in man were investigated. The calcium fluoride tablets were more than 50% dissolved after 1 hour in simulated gastric fluid, but were negligibly soluble in water or phosphate buffer. In spite of the moderate dissolution of the calcium fluorid tablets seen in vitro in simulated gastric fluid, no absorption of fluoride was apparent in human volunteers as measured by plasma levels; values at all timepoints were ~20 ng/mL plasma. In contrast, a marked elevation of plasma fluoride levels (~5 -6 times pre-dosing levels) to ~100 -120 ng/mL plasma was seen in the volunteers administered sodium fluoride. The bioavailability of fluoride from calcium fluoride in vivo is therefore shown to be very low (Afseth et al, 1987), however it was acknowledged that this may be due to the physical form in which it was administered in this study. The absorption of fluoride was investigated in pregnant female volunteers administered calcium fluoride or sodium fluoride supplements. Elevated maternal fluoride levels were seen in all treated groups and were comparable following supplementation with sodium fluoride or calcium fluoride. In all groups, umbilical cord fluoride levels were consistently slightly higher than maternal levels. The study therefore indicates the comparable bioavailability of sodium fluoride and calcium difluoride (Caldera et al, 1988). The study of Smith & Leverton (1934) indicates that the bioavailability of fluoride from calcium difluoride is comparable to more water souble salts at low levels of exposure causing mild effects, but is much lower at higher levels of exposure.

No specific data on the dermal absorption of calcium difluoride are available, however the low water solubility of the substance and its ionic nature indicate that dermal absorption is likely to be negligible.

Acute toxicity

The results of an acute oral toxicity study report an acute oral LD50 value of 4250 mg/kg bw in the rat (Tarasenko et al, 1977). Another older study (Simonin & Pierron, 1937) reports an oral LD50 value of >5000 mg/kg bw in the guinea pig. The low toxicity of the substance is confirmed in a modern guideline-compliant study in the rat (Cords & Lammer, 2010), which reports an LD50 of >2000 mg/kg bw at the limit dose.

The acute inhalation toxicity of calcium fluoride was studied by nose-only exposure of one group of five male and five female rats for a 4 hour period. The test atmosphere contained calcium fluoride dust (MMAD 2.8 um) at the limit concentration of 5.07 g/m3. After exposure the animals were kept for a 14-day observation period, then necropsied. Treatment-related effects seen during exposure were limited to a slightly decreased breathing rate in two animals. No further abnormalities were detected during after exposure or during the 14 day observation period. A low overall body weight gain was seen in females. At necropsy, treatment related macroscopic changes were limited to red/pink discolouration of the lungs in two females. The 4-hour LC50 value of calcium fluoride dust was found to be greater than 5.07 g/m3 for both sexes under the conditions of this study (Mommers, 2002).

No data are available for acute dermal toxicity and a waiver is proposed for this data requirement. Calcium fluoride is shown to be of inherently low toxicity by the oral, inhalation and intraperitoneal routes. Dermal absorption is also likely to be insignificant for this inorganic salt of low solubility, therefore it can be reliably predicted that the acute dermal toxicity of the substance will be very low. A study of acute dermal toxicity is scientifically unjustifed and additionally cannot be supported for reasons of animal welfare.

A single dose of calcium fluoride was administered by intraperitoneal injection to gravid female mice on day 9 of gestation at dose levels of between 25 and 6400 mg/kg bw. The acute intraperitoneal LD50 of calcium fluoride in gravid female mice was calculated to be 2778 mg/kg bw under the conditions of this study (Stratmann et al, 1979); the same authors report an LD50 value of 2638.27 mg/kg bw in a later paper (Stratmann & Eifinger, 1981), this value may represent a re-interpretation of the same data.

Tsunoda & Lu (1985) investigated the bioavailability of fluoride administered in different forms (calcium fluoride and sodium fluoride). In the group administered sodium fluoride, serum levels increased rapidly from background to peak at 0.341 ppm at 30 minutes. Levels subsequently dropped gradually to reach background at 24 hours. Urinary excretion over 24 hours accounted for 48.1% of the administered fluoride. In the group administered calcium fluoride, serum fluoride levels were slightly raised after one hour and reached a peak concentration of 0.073 ppm at two hours. Individaul serum fluoride values were much more variable than in the other group. Urinary excretion over 24 hours accounted for 8.5% of the administered fluoride. The authors conclude that the gastrointestinal absorption of fluoride is influenced by the solubility of the form in which it is administered.

Irritation

Calcium fluoride was found to be non-irritant in a modern proprietary guideline and GLP-compliant study (Prinsen, 2002) and was found to be a slight eye irritant in a modern proprietary guideline and GLP-compliant study (Prinsen, 2002).

Sensitisation

A modern LLNA (Remmele, 2010) demonstrates that calcium difluoride does not have skin sensitisation potential. There is no indication that the substance is a respiratory sensitiser.

Repeated dose toxicity

In an oral study study using 12 paired groups of albino rats (Lawrenz et al, 1939), the authors administered fluoride in the form of calcium fluoride or cryolite in the drinking water for 14 weeks. Total fluoride intake (from the basal diet and drinking water) amounted to a dose level of approximately 0.75 mg/kg bw/d. Bodyweight gain and food consumption were retarded in both dose groups. Clinical signs were limited to transient haematuria in both groups, and the appearance of dental striations in all animals from Week 8 -10. Analytical derminations at necropsy revealed fluoride retention of approximately 59%, and that the large majority of the fluoride in the body was present in the skeleton (~96%). No differences were apparent between the treated groups. The authors conclude that the effects of fluoride from these two insoluble salts are comparable.

Smith & Leverton (1934) investigated the comparative toxicity of various forms of inorganic fluoride in a 6 -week feeding study in male rats. They noted that overt effects of calcium difluoride toxicity (bodyweight reduction, mortality) were seen only at very high concentrations compared to other, water-soluble fluorides. In contrast, mild dental effects were seen at comparable fluoride levels for all of the compounds investigated, however the more severe effects were only seen at much comparatively much higher concentrations of calcium difluoride. The results of the study therefore indicate that the toxicity of calcium difluoride is markedly influenced by its low water solubiliy.

The much greater water solubility of sodium fluoride (41300 mg/L) compared to calcium fluoride (15 mg/L) means that the bioavailability of fluoride from NaF is likely to be much greater than that of fluoride from CaF2 and therefore represents a worst case. The toxicity of NaF has been extensively investigated in drinking water studies performed by the UES NTP (1990). 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 nouse 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.

The inhalation toxicity of an aerosol of the low solubility salt aluminium trifluoride was investigated in a sub-acute 28 day study in Wistar rats. Groups of 5 rats/sex were exposed to target concentrations of 0 (control), 1, 7 or 50 mg/m³, for 6 hours/day, 5 days/week for 28 days (a total of 20 exposures). No treatment-related abnormalities were noted during exposure. There were no treatment-related effects on food consumption, food conversion efficiency and body weight gain. In the high-dose males there was a relative and absolute increase in the concentration of neutrophils, an increase of the globulin concentration, and an increase in both absolute and relative liver and lung weights. The increase in absolute and relative lung weights was also seen in high-dose females. There were treatment-related histopathological changes in the lungs of all exposed animals and in the tracheobronchial lymph nodes of high-dose males and females. In the lungs of animals from the high-dose group, multifocal alveolar 'pigment' macrophages with particulate material in their cytoplasm were accompanied by inflammatory changes. In the tracheobronchial lymph nodes of all rats in the high-dose group, the pigment was seen as deposits of (phagocytised) particulate material in the cortex and medulla. In the lungs of the low and mid-dose group, only very slight focal (low-dose) or very slight multifocal (mid-dose) macrophages containing a single or a few pigments were seen. Since phagocytosis and processing of foreign material is a normal function of alveolar macrophages, the presence of pigment macrophages in the lungs of the animals of the low and mid-dose groups was not considered to be an adverse toxicological effect. The 28 day inhalation NOAEL for aluminium trifluoride was 7 mg/m³.

Genetic toxicity

No evidence of mutagencitiy was reported in a modern Ames test performed with calcium difluoride (Schulz & Landsiedel, 2010) in Salmonella typhimurium strains TA1535, TA100, TA98, TA1537 and in E. coli strain WP2 uvrA. No evidence of mutagenicity was observed in a recent mammalian cell gene mutation assay (V79/HPRT) performed with calcium difluoride (Wollny, 2010).

No evidence of cytogenicity was seen in V79 cells in a modern study (Hall, 2010).

Carcinogenicity

High quality NTP studies in the rat and mouse are available for sodium fluoride The EU RAR for HF concludes that the data are sufficient to suggest that fluoride is not carcinogenic in animals.

Reproductive toxicity

Araibi et al(1989) report adverse 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. Chinoy et 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.

The results of these studies are consistent, however 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 also notable that the findings of these published investigative studies of non-standard design contrast with the total absence of reproductive toxicity at comparable dose levels in the FDA studies reported below.

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.

FDA studies

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 detailed investigations by the same authors did not reveal any effects on spermatogenesis in F1 males (Sprandoet 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 indicated 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 other 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.

The developmental toxicity of calcium fluoride and sodium fluoride was investigated in the mouse. Pregnant female mice were administered the substances in the drinking water or by intraperitoneal injection during gestation. Treatmnet caused structural changes in the jaw and teeth of offspring, with retardation of skeletal calcification. Calcium fluoride was reported to be more toxic, possible due to the higher fluoride content; high doses of both substances caused resorption or foetal death (Fleming & Greenfield, 1954).

In a rat developmental toxicity study (NTP, 1994; Heindel et 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; Heindel et al, 1996) at dose levels of up to 400 ppm sodium fluoride (equivalent to 14 mg/kg bw/d fluoride from all sources).

Stratmann et al (1979a,b; 1981) studied the effects of calcium fluoride administration to mice by sinhle intraperitoneal injection on Day 9 of gestation, by dietray administration throughout gestation or over several generations. Embryotoxic effects of calcium fluoride were noted in this study only at very high single intraperitoneal dose levels (1600 mg/kg bw or higher), very high dietary concentrations in the repeated dose phase (20.48g%) or in the generation study (10.24g% and higher). The authors note that the negative effects of the substance on embryogenesis are slight compared to other fluoride compounds and conclude that the substance shows no effects at dose levels relevant for caries prophylaxis and is 'absolutely safe'.

DNEL derivation

In contrast to other, more soluble inorganic fluoride salts, calcium difluoride is demonstrated to be of very low acute toxicity by all routes investigated. There is no evidence of irritancy or sensitisation and calcium difluoride (in common with other salts) is not considered to be genotoxic. The results of repeated dose toxicity studies show that calcium difluoride exhibits typical fluoride toxicity, with dental effects seen in a drinking water study in the rat. Repeated dose effects on the teeth and the skeleton are common to all inorganic fluorides. The low solubility of calcium difluoride compared to other fluoride salts is notable, and it is likely that the low acute toxicity of calcium is a consequence of its low solubility and hence its bioavailability. Oral LD50 values of approximately 30 -80 mg/kg bw are reported for the highly soluble sodium fluoride; values for calcium difluoride are two orders of magnitude higher. The assumption of the low bioavailability of calcium difluoride is not totally supported by the results of literature studies using oral administration, which report very variable levels of absorption. It is clear that other influences including the form of the dose and pH may also affect the bioavailability of calcium difluoride.

In practice, the parameter of interest is the bioavailability of calcium difluoride following inhalation exposure. No data are available for calcium difluoride, however the results of a 28 -day study with aluminium fluoride do not reveal any systemic effects attributable to fluoride at the highest exposure concentration of 50 mg/m3. Findings in this study were limited to increased liver weight (not considered to be attributable to fluoride), increased lung weights and histopathology secondary to particle deposition in the lung.

Systemic toxicity following the inhalation of calcium difluoride is possible, but is likely to be much less than for other fluoride salts due to its low solubility and consequent likely low bioavailability. The relevant study for calcium difluoride is considered to be the 28-day inhalation study with the insoluble salt aluminium fluoride, which is considered to be a relevant read-across substance. Evidence of systemic toxicity in this study was limited to increased liver weight and associated minimal clinical chemistry changes (altered A:G ratio) at the highest exposure concentration; findings are not representative of fluoride toxicity, but are characteristic of the effects of aluminium on the liver. It is therefore concluded that there is no evidence of systemic fluoride toxicity in this study. Local effects were also apparent in this study; increased lung weights at the highest exposure concentration were associated with the accumulation of alveolar pigment macrophages containing particulate material and very slight inflammatory change.

The IOELV for inorganic fluorides of 2.5 mg/m3as listed in Commission Directive 2000/39/EC is considered to be appropriate for calcium difluoride. The IOELV (equivalent to 5 mg/m3calcium difluoride) covers all inorganic fluoride salts including the highly soluble salts, and therefore can be considered to be a conservative approach for calcium difluoride, which is of low solubility and low bioavailability following inhalation.

Guidance from ECHA (Section R8) states that'a registrant is allowed to use an IOEL as a DNEL for the same exposure route and duration, unless new scientific information that he has obtained in fulfilling his obligations under REACH does not support the use of the IOEL for this purpose. This could be because the information obtained is more recent than the information that was used to support setting the IOEL at EU level and because it leads to another value being derived which requires different risk management measures (RMMs) and operational conditions (OCs).'

The additional data for the read-across substance aluminium fluoride do not show any effects of fluoride and shows only local effects attributable to particle overload at the highest exposure concentration of 50 mg/m3. This study is therefore not considered to constitute information which would result in different RMMs or OCs.

Systemic DNEL values

Systemic inhalation DNEL value

The IOELV of 2.5 mg/m3for inorganic fluorides (equivalent to 5 mg/m3calcium difluoride) is used as the DNEL for systemic effects following inhalation and is also protective of local effects due to particle deposition. The systemic DNEL inhalation value is proposed for long-term exposure as the substance is shown to be of very low acute toxicity; an acute systemic DNEL values is therefore not derived.

Systemic dermal DNEL value

Calcium difluoride exhibits typical fluoride toxicity following oral exposure. No repeated dose dermal toxicity data are available. The low water solubility of the salt and its ionic nature means that dermal absorption is likely to be negligible. Systemic dermal DNEL values are therefore not derived.

DNEL values for local effects

Calcium difluoride is not a skin irritant or sensitiser. No local effects have been observed in inhalation studies with the exception of findings secondary to particle overload. In the absence of relevant effects, dose-response data are absent and a quantitative dose descriptor is not available. DNEL values for local effects are not derived for calcium difluoride.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.02 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

General Population DNEL values

The general population may be directly exposed to calcium difluoride through some of the supported uses of the substance.

The indirect exposure of the general population to calcium difluoride is of limited relevance. The substance will be solubilised slowly in the environment to form fluoride and calcium ions and will further interact with other ionic species naturally present in the environment. The contribution of the substance to the total fluoride intake of the general population is likely to be very small in comparison to the contribution of fluoride from natural sources, predominantly through the diet and drinking water.

DNEL values for systemic effects

The critical long-term systemic effect for exposure to inorganic fluoride salts including calcium difluoride is skeletal and dental fluorosis. The IOEL value for inorganic fluorides of 2.5 mg/m3fluoride (equivalent to approximately 5 mg/m3calcium difluoride) is designed to protect against the systemic effects of fluoride exposure in workers (Directive 2000/39/EC). This value is considered to be appropriate for calcium difluoride as the substance is of low water solubility and is of low bioavailability following inhalation exposure. No specific data are available for dermal absorption, however the dermal absorption of fluoride from calcium difluoride is not considered to be likely, given the low water solubility and ionic nature of the substance. Investigations of oral bioavailability reported in this dossier have given very variable results with findings strongly influenced by the concentration and physical form of the administered substance. A conservative position would therefore be to assume extensive (100%) oral absorption.

Systemic inhalation DNELvalue

A systemic inhalation DNEL for the general population may be derived by the application of an assessment factor of 5 to the worker DNEL value of 2.5 mg/m3fluoride (5 mg/m3calcium difluoride) to take into account the potential greater sensitivity, breathing rate (20 m3/day) and longer potential exposure period (24 hours/day) of the general population.

A long-term systemic worker DNEL value of 0.5 mg/m3is therefore calculated. Data indicate that the bioavailability of fluoride from calcium difluoride is low, therefore this value is considered to be sufficiently protective.

Oral systemic DNEL value

An alternative approach to deriving a systemic oral DNEL would be to allow exposure to the substance to account for a proportion (10%) of the estimated total daily fluoride intake from all sources (predominantly diet and drinking water) of 6 mg/day. An oral DNEL of 0.01 mg/kg bw/d fluoride, equivalent to 0.02 mg/kg bw/d calcium difluoride can be derived, assuming a bodyweight of 60 kg.

While it is recognised that the selection of a level of 10% of background intake is somewhat arbitrary, however this level is chosen as one that would not be expected to add significantly to the overall exposure of the general population to fluoride from all sources.

The systemic DNEL inhalation and oral values are proposed for long-term exposure as the substance is shown to be of very low acute toxicity; acute systemic DNEL values are therefore not derived.

Dermal systemic DNEL value

A dermal systemic DNEL value is not derived as dermal absorption of fluoride from calcium fluoride is not predicted.

DNEL values for local effects

Calcium difluoride is not a skin irritant or sensitiser. No local effects have been observed in inhalation studies with the exception of findings secondary to particle overload. In the absence of relevant effects, DNEL values for local effects are not derived for calcium difluoride.