Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity data are not available for zinc difluoride. However, studies conducted with soluble zinc and fluoride substances were included in the dossier. For information please refer to the endpoint discussion for zinc and fluoride.

Key value for chemical safety assessment

Mode of Action Analysis / Human Relevance Framework

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 zinc moiety (or one of its readily soluble salts). This way forward is acceptable, since zinc difluoride dissociates to the fluoride anion and the zinc cation upon dissolution in aqueous media.

Once the individual constituents of zinc 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 zinc cation and the fluoride anion.

More detailed information on read-across can be found in IUCLID 0 "category".

 

Zinc(II):

The administration of zinc oxide at a dose level of 40 mg/kg bw/day for a period of 120 days in the diet of Sprague-Dawley female rats did not lead to any noticeable clinical toxicity. In the high zinc groups a significant elevation of serum cholesterol was observed as the only biologically relevant effect which was independent from the vitamin A co-administration (SCCNFP, 2003).   Apart from animal studies a series of human experimental studies have also been published. The following reports confirm safe exposure levels in humans: In a double-blind trial, 13 humans received 200 mg zinc sulphate (corresponding to about 1.35 mg Zn-ion) three times a day for 18 weeks, while 14 humans received a placebo. No signs of toxicity associated with the zinc treatment were reported (Hallbook & Lanner, 1972). In a study of Greaves and Skillen also no toxicity was seen in 18 humans after administration of 220 mg zinc sulphate (about 150 mg Zn-ion) 3 times a day for 16-26 weeks (SCCNFP, 2003).   Based on human studies the SCF established a no observed adverse effect level (NOAEL) of 50 mg/person per day for zinc, and this was subsequently confirmed by EFSA in 2006 and 2014 (EC, 2003; EFSA Scientific Committee and NDA Panel, 2006; EFSA NDA Panel, 2014). The NOAEL of 50 mg/person per day is based on the absence of any adverse effects on a wide range of relevant indicators of copper status (as the critical endpoint) in the studies by Davis et al. (2000), Milne et al. (2001) and Bonham et al. (2003a, b) (EFSA CEF Panel, 2016).

 

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 to7.85 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/kgbw/day with a LOAEL at 3.2 mg F/kgbw/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.