Fluorine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.58 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other:

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.16 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other:

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.58 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.16 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

Summary of toxicology

Fluoride, rather than fluorine, is the agent that is toxicologically active systemically, since fluorine is too reactive to be absorbed unchanged. The critical effects of chronic exposure to low concentrations of fluorine are due to the systemic effects of fluoride and therefore studies with other inorganic fluoride, such as NaF, will provide insight in fluoride toxicity also applicable to fluorine.

 

Toxicokinetics

When inhaled, absorption of fluorine gas can be expected to be virtually complete. Fluorine is converted to fluoride, and then distribution and retention will follow the normal patterns for inorganic fluoride (WHO, 1984). The absorption of inorganic fluoride across mucous membranes is passive and is independent of the fluoride source. 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

According to Annex VI of CLP, Fluorine is classified as Acute Toxicity Inhalation, Category 2 (H330, Fatal if inhaled). However, a published study of non-standard design shows that the 60-minute LC50 values for rats and mice exposed to fluorine are 185 ppm and 150 ppm respectively (Keplinger and Suissa, 1968).

Irritation and corrosivity

Fluorine is classified according to the CLP Regulation (EC) 1272/2008 as Corrosive Cat. 1A (H314).

Sensitisation

The local dermal effects of fluorine exposure will be dominated by irritation/corrosion and sensitisation is considered to be unlikely. Additionally it is noted that there is no evidence that fluoride is a skin sensitiser.

 

Repeated dose toxicity

No oral studies have been performed with fluorine, however comprehensive data are available for sodium fluoride. 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 fluorine will be dominated by local irritation/corrosion. There is no evidence of significant dermal absorption of fluorine under exposure conditions where the integrity of the skin barrier is maintained.

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 other studies conducted over longer exposure periods give over-all NOAEL for repeated inhalatory exposure in male and female rats of 0.72 mg/m3 (actual HF concentration) for a 6 hours per 5 days per week for 91 days exposure regimen (Placke et al., 1991) and a NOAEL of 0.88 mg/m3 (actual HF concentration) for a 6 hours per 5 days per week for 2 weeks (Placke et al., 1990). No adverse effects were noted at these concentrations. At higher concentrations death, tissue irritation, dental malformations, slight changes in haematological and clinical chemistry parameters, and changes in several organ weights were observed.

 

Genetic toxicity

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 lynmphoma assay (NTP, 1990). Sister chromatid exchange and chromosomal aberrations are reported in an additonal NTP study. 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.

 

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).

 

Reproductive toxicity studies

No effects on reproduction were seen at the highest dose level of 250 ppm in a guideline-comparable two-generation rat study (FDA, Collins et al, 2001). The EU RAR for HF also considers the data available for the reproductive toxicity of NaF and concludes that the FDA study is 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.

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). Based on the available data, an overall NOAEL for maternal toxicity and developmental effects of 11.12 mg F-/kg b.w./d can be derived.

Human volunteer studies

The irritating properties of fluorine have been studied in a human volunteer study. Keplinger and Suissa (1968) exposed five adult volunteers (19 -50 years of age) to concentrations up to 100 ppm via a

face mask. These tests were designed to test for irritation only. A concentration of 10 ppm (15.8 mg/m3) for up to 15 min was reported to be non-irritating to the eyes and nose. A concentration of 25 ppm for 5 min caused slight irritation to the eyes but could be inhaled without respiratory difficulty. A concentration of 50 ppm for 3 min was irritating to the eyes and slightly irritating to the nose. Concentrations of 67 to 100 ppm for 1 min were irritating to the eyes and nose and became uncomfortable after a few seconds. The subjects did not inhale at the 100 ppm concentration. The 100 ppm concentration caused slight irritation of the skin and a “sticky” feeling.According to the authors, the eyes were the most sensitive indicator of irritation in humans. Keplinger and Suissa (1968) also reported that a few repeated exposures at a concentration of 10 ppm for 3 to 5 min every 15 min over a 2- to 3-h time period caused only slight irritation to the eyes and skin. No respiratory difficulty was reported.

Acute/short-term and long term DNELs (inhalation)

In Appendix R.8-13 of the Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health (November 2012, ECHA) it is noted that "When an EU IOEL exists the registrant may, under conditions as described below, use the IOEL in place of developing a DNEL. 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)".

SCOEL has derived a TLV-TWA of 1 ppm (1.58 mg/m3) and a TLV-STEL of 2 ppm (3.16 mg/m3) for occupational exposure to fluorine to minimize the potential for eye, skin and mucous membrane irritation (SCOEL/SUM/56 final December 1998). A TLV-STEL is recommended to provide additional protection from irritant effects based on the data from a 15-minute exposure of human volunteers at 10 ppm fluorine that produced slight irritation of the eyes and skin. These values are considered to be adequately protective for systemic effects of fluorine (fluorosis). 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

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

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

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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

DNEL values for the general public are of limited relevance, as exposure to fluorine is not predicted. However, the deposition of fluorine may contribute to the total fluoride intake of the general public and therefore a long-term oral DNEL for the general population was calculated. In case of release to the environment, fluorine will react immediately with the surrounding material and will predominantly be present as fluoride which will further interact with other ionic species naturally present in the environment. Fluorides are naturally occurring components of rocks and soil. One of the more commonly used fluoride salt is sodium fluoride; its principal use is for the prevention of dental caries. The general population can be exposed to fluoride through the consumption of fluoridated drinking water, food, and dentifrices. Exposure estimates to fluoride from all sources in Europe show total intakes from 0.5 to 1.2 mg/day, when no fluoridated salt or fluoride containing tooth paste are used, and no supplements are taken. In case where fluoridated salt is used and fluoridated water is drunk and used for the preperation of food and tea, the sum of fluoride intake could reach 6 mg/day, without taking into account toothpaste use (EFSA, 2008).

Long-term - DNEL for systemic effects

The critical effect of chronic exposure to fluoride is skeletal fluorosis. The SCOEL have recommended an IOEL value of 1.0 ppm (1.58 mg/m3) for fluorine to protect against the systemic and local effects of fluoride exposure in workers. 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 0.40 mg/m3. However the potential fluoride exposure resulting from this DNEL is equivalent to 8 mg/day (average breathing volume of 20 m3/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 for fluoride. On the same basis (i. e. allowing for fluoride intake to account 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.

 

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