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Description of key information

Repeated dose toxicity data are not available for strontium difluoride. However, studies conducted with soluble strontium and fluoride substances were included in the dossier resulting in an NOAEL für strontium difluoride of 14.2 mg/kg bw/day that is used for the hazard assessment of strontium difluoride.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
14.2 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study is used as key study for this endpoint, since the study fulfils the requirements of the current test guideline for oral sub-chronic exposure to a great extent, but the study was not performed under GLP requirements (Klimisch score=2).
System:
endocrine system
Organ:
thyroid gland

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the fluoride moiety and the strontium moiety (or one of its readily soluble salts). This way forward is acceptable, since strontium difluoride dissociates to the fluoride anion and the strontium cation upon dissolution in aqueous media.

Once the individual constituents of strontium difluoride become bioavailable (i.e. in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated substance can be described by the toxicity of the “individual” constituents. Since synergistic effects are not expected, the human health hazard assessment consists of an individual assessment of the strontium cation and the fluoride anion.

For more detailed information on read-across please refer to the report attached on IUCLID section 13 "SrF2_Read Across Assessment Framework Report"

 

Strontium:

In a sub-chronic feeding study by Kroes et al. (1977) SPF Wistar rats (40-60 g of body weight, 10 males and 10 females per group) received strontium chloride hexahydrate in a semi-purified diet at dose levels of 0, 75, 300, 1200, and 4800 ppm for 90 days. The diet contained adequate levels of Ca, Mg, P and vitamin D3. Growth, behaviour, food intake and food efficiency were not affected in the 90-day study.

No differences in clinical chemistry were noted, except of an indication of increased alkaline phosphatase activity in the highest dose group. Urinalysis showed no differences in the groups. The levels of Ca, Mg and P in blood were similar for all dose levels and the Ca/P ratio was constant.

In males, thyroid weights were significantly increased in the 1200 and 4800 ppm groups. Although, no clear explanation of this finding could be given it was regarded as treatment-related. In females, pituitary weights were significantly decreased in the 300 and 4800 ppm group, but not in the 1200 ppm group, and this finding was regarded as difficult to interpret. Glycogen depletion of the liver was noted in the highest dose group. However, this was may be caused by stress, starvation or diurnal rhythm and not by treatment with the test substance.

Detectable amounts of strontium in blood and muscle were only noticed at the dose of 4800 ppm. The strontium content in bone was increased at all dose levels having a constant level from 4 weeks onwards (steady-state level).

No treatment-related changes were observed in the X-ray photographs and on histopathological examination except, slight changes in the liver (glycogen depletion) and thyroid (activation). Thus, upto the highest dose of 4800 ppm no rachitic changes occurred.

Considering the increased concentrations of strontium in the bone as a non-toxic effect, a NOAEL of 300 ppm SrCl2* 6 H2O can be derived from this study based on the weight changes of thyroids at the doses of 1200 ppm (LOAEL) and 4800 ppm, and thyroid activation at 4800 ppm. No data on daily food intake are available in order to calculate daily dose levels. According to the estimation mentioned above, the NOAEL of 300 ppm strontium chloride hexahydrate corresponds to a dose of 30 mg/kg bw/d, equal to 14.2 mg SrF2/kg bw/d.

 

Fluoride:

Effects of excessive exposure to fluorides on the skeletal system have been identified as the most sensitive endpoint. Effects include reduced bone strength, increase risk of fractures and/or skeletal fluorosis (stiffness of joints, skeletal deformities). For quite some time, the occupational exposure limit value for fluorides was set at 2.5 mg F/m³, e.g. SCOEL (1998), as supported by the findings by Derrberry et al. (1963) and Kaltreider et al. (1972). These authors had not reported effects on the skeletal system for workers exposed for 10 years to an average of 2.4 or 2.65 mg F/m³.

However, other and partly more recent human and animal data suggest that a limit value of 2.5 mg F/m³ may not be sufficient to protect humans against effects on the skeletal system: Assuming full absorption, and a shift-breathing volume of 10 m³ (per 8-hours), a worker working in an atmosphere containing 2.5 mg F/m³ would absorb 25 mg F/day. Further, as summarised above, the additional background fluoride intake from food, drinking water and dental care products may add up to a couple of mg F/day or even over 6 mg F/day in worst case scenarios, thus leading to worst case estimates of combined exposure of more than 30 mg F/day.

In contrast, according to US DHHS (1991) and WHO (2002), skeletal fluorosis (clinical phase III) may result when exposed to 20 mg F/day for more than 20 years.

Multiple sources support the conclusion that a safe total daily intake of fluoride should at least be below ca. 14 mg F/day.

- EPA (1985) reported no skeletal fluorosis when fluoride in drinking waters was 4 mg F/L (i.e. ca. 8 mg F/day assuming a consumption of 2 litres/day).

- The study by Li et al (2001) suggested no increased risk for bone fractures over 20 years at up to 7.85 mg F/day, but increased risk for humans exposed to 14.13 mg F/day.

- The study by Hillier et al. (2000) in which no increase in the prevalence of hip fractures was seen at 0.2 - 0.3 mg F/day is supportive.

- The animal study by Turner et al. (2001) suggested a NOAEL for effects on bone density of 0.94 mg F/kg bw/day with a LOAEL at 3.2 mg F/kg bw/day. According to the authors, the NOAEL and LOAEL found in the rat study correspond to drinking waters concentrations for humans of 3 mg F/L and 10 mg F/L, respectively. Assuming a water intake of 2 L/day, these can be converted to corresponding daily doses of 6 mg F/day (NOAEL) and 20 mg F/day (LOAEL). Further, assuming a 10 m³ inhalation volume (for an 8 hour shift), these correspond to 0.6 mg F/m³ (NOAEC) and 2 mg F/m³ (LOAEC).

Based on these considerations, a workplace exposure limit (i.e. the DNEL) is derived at 1 mg F/m³. As a worst case assumption, 100% systemic absorption may be assumed, which together with a 10 m³ shift breathing volume results in an estimated maximum daily dose at the workplace of 10 mg F/day. Note: it appears unrealistic to assume that a worker spends a full 8-hour shift in an atmosphere containing 1 mg F/m³. Further, depending for example on the particle size, not all particles will be inhaled (some will not be inhaled at all, others will be exhaled). On the other hand, there may be some contribution of fluorides absorbed via the skin (dermal exposure), or also of inadvertent ingestion (hand-to-mouth transfer). Whereas the latter cannot be quantified reliably and whereas such additional dermal and oral exposure would be expected on under circumstances of poor industrial hygiene, a 100% total systemic absorption is maintained, still presenting a conservative scenario for the risk assessment. Acknowledging that background intake due to drinking water, food, dental care products etc. may exceed 5-6 mg F/day in highly worst case scenarios, a typical background intake would rather be in the of range of 0.5-2 mg F/day. Adding a worst case workplace exposure of 10 mg/day and a typical background exposure of 2 mg/day will still result in a safe total fluoride intake for workers.

Thus, the DNEL of 1 mg F/m³ is adequately protective, even when considering that workers can - in addition to the inhalation route - be further exposed to fluorides via other routes, i.e. dermal and/or oral (hand-to-mouth-transfer) at the workplace, and also due to a background intake via diet, drinking water and dental care products.

Justification for classification or non-classification

Based on the results described above, classification for repeated dose toxicity is not warranted.