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
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: Based on SCOEL SUM/56 prepared in 1998 and listed in Commission Directive 2003/39/EC, the IOELV for inorganic fluorides of 2.5 mg/m3 equates to 5 mg/m3 calcium difluoride
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

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/m3 for inorganic fluorides (equivalent to 5 mg/m3 calcium 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:
1 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: SCOEL calculations adjusted to take account of general population exposure
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

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 hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

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/m3 fluoride (equivalent to approximately 5 mg/m3 calcium 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/m3 fluoride (5 mg/m3 calcium 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 1 mg CaF2/m3 is 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.