Lithium hexafluorophosphate(1-)

Endpoint summary

Description of key information

Skin corrosion is expected to occur on contact.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Dose descriptor:

NOAEL

133 µg/kg bw/day

Study duration:

chronic

Species:

other: man

Quality of whole database:

Reliable tolerable upper limit for daily intake by the general population.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Dose descriptor:

NOAEC

2 mg/m³

Study duration:

chronic

Species:

other: man

Quality of whole database:

Reliable workplace exposure limit protective against adverse health effects.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Dose descriptor:

NOAEC

1.12 mg/m³

Study duration:

subacute

Species:

other: man

Quality of whole database:

Extrapolation of NOEC from findings to LiPF6 solid from the gaseous hydrolyis product HF is questionable.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Given the ease of passage through the skin for the fluoride ion hydrolysis product, oral results can be considered to apply to skin contact.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Lithium hexafluorophosphate is reactive and unstable in water and air. Reaction in contact with water proceeds rapidly, with release of hydrogen fluoride (forming hydrofluoric acid). Such local generation of hydrogen fluoride/hydrofluoric acid at the site of contact with skin or other membranes, with consequent potential for serious local tissue damage, is a major cause of the observed corrosivity of the substance, and secondary tissue necrosis due to localised free fluoride ion concentrations is also a likely contributor to this (Kirkpatrick Enion and Burns, 1995): delayed onset of deep tissue damage and pain is known after skin contact with HF solutions below 20% in concentration (US ATDSR, 2001). Ethical and practical reasons therefore make it inappropriate to conduct repeat-dose toxicity testing of lithium hexafluorophosphate in animals; since information is available on systemic toxicity of the ultimate hydrolysis products hydrogen fluoride, lithium/Li+, fluoride/F- and phosphoric acid/phosphate, such testing is also scientifically unnecessary. In accordance with Annex XI, 1.2 of the REACH Regulation testing is not scientifically necessary based on weight-of evidence approach (see separate read-across justification in Section 13). On humane grounds, as indicated in article 15, 2 of Directive 2010/63/EU, such testing (expected to involve severe pain, suffering or distress likely to be long-lasting) should not be performed.

 

HF

Exposure of female rats to 1 mg/cu.m, 6h/day over 1 month caused lesions of the respiratory tract (atrophy, local oedema of the bronchial mucosa; peribronchial hyperplasia); damage to dental enamel and structural change in bones were also seen (EU Risk Assessment Report on HF, EC 2001: English summary of Russian study). Although a subchronic NOAEL arising from a 90-day rat inhalation study is cited in various EC, US and Australian governmental or regulatory reviews and is converted to a duration corrected NOAEL (presumably adjusted to model occupational or population exposure) in the OECD SIAR document for hydrogen fluoride, it has been noted (US NRC Committee on Toxicology, 2009) that the study protocol employed may not have included examination of anterior nasal tissue (external nares and nasal vestibule) most susceptible to HF-induced lesions; for this reason, this expert committee concluded that published animal studies provide no clear NOAEL for HF. The same source cites a US NRC review of fluoride in drinking water conclusion that establishment in rats or mice of comparable physiological levels or health effects to those seen in man requires markedly (5 – 18 times) higher fluoride intakes (US NRC, 2006).

 

In a human study of HF inhalation (Largent et al, 1960 and 1961), 5 volunteers were exposed 6h/day to concentrations of 0.74 – 1.64 mg/cu.m for 15 days, or 2.21 – 6.64 mg/cu.m for 50 days. From descriptions of this study in two different publications, the EU Risk Assessment Report on HF concludes that some effects (presumably non-systemic indicators of irritation) were likely to have occurred at the lowest exposure level of 0.74 mg/cu.m. In a 1998 recommendation document (SCOEL, 1998), the Scientific Committee on Occupational Exposure Limits noted that HF absorption via inhalation is expected to be near complete, with critical effects of chronic exposure to low concentrations being due to systemic fluoride toxicity; their recommended 8h TWA value of 1.5 mg/cu.m (as F-) for HF was accepted as an IOELV in Directive 2009/39/EC.

 

Fluoride

Chronic exposure to inorganic fluoride, with consequent systemic distribution of fluoride, has been widely studies in animals and man. Total inorganic fluoride intake in the, from nonwater plus fluoridated drinking water sources, has been estimated to be up to 258 µg/kg/day in infants and up to 79 µg/kg/day in adults (US NRC, 2006). Estimates of total intake in theare somewhat lower: 127 and 42 µg/kg/day for children and adults respectively (MRC, 2002).  In various areas of the UK where naturally occurring levels of fluoride in water fall below 1 mg/l, inorganic (commonly sodium) fluoride is added to drinking water to raise fluoride content to this level, for the purpose of preventing dental caries. Fluoride concentrations of 2 mg/l and higher in drinking water have been reported to cause adverse effects: ≥2 mg/l causing dental fluorosis in children, ≥8 mg/l causing skeletal fluorosis in all ages (occupational exposure by inhalation at 5-20 mg/cu.m also also causing severe fluorosis) (MRC, 2002). Human (general population) no-effect levels for several adverse affects have been calculated for total fluoride intake (Theissen, 2007):

-  impaired thyroid function, NOEL 30 µg/kg/day

-  skeletal fluorosis (Stage II), NOEL 40 µg/kg/day

-  neurotoxicity, NOEL 50 µg/kg/day.

The US EPA have set a reference dose for inorganic fluoride of 80 µg/kg/day, and this has been concluded to be protective against severe dental fluorosis in children and adverse health effects of fluoride in adults, including increased bone fracture risk (US EPA (OW), 2010). This conclusion has been questioned, based on reports that sensitive human subpopulations (e.g. cases of iodine deficiency) may suffer adverse effects after intake at 10 – 30 µg/kg/day (Thiessen, 2011); however, since unavoidable fluoride intake is unlikely to be markedly less than 30 µg/kg/day there can be little justification for claiming a Human NOEL at or below this figure. Tolerable maximum intake levels for fluoride have been set in Europe (EFSA, 2008a): these range from 1.5 mg/day for infants 1 – 3 years old (= 126 µg/kg/day for the EFSA default mean weight value, 11.9 kg) to 7 mg/day for adults (= 100 µg/kg/day for a 70 kg adult). Accordingly a tolerated chronic intake of 100 µg/kg/day (as F-) is considered suitable for use in risk assessment.

 

Given that evidence that rats may require higher chronic exposure to fluoride than man to achieve comparable plasma and bone concentrations, it is appropriate to use human toxicity data for fluoride to establish effects of long-term, repeat exposure.

 

Lithium

 Average dietary intake of lithium by American adults has been reported to be 0.65 – 3.1 mg/kg/day, and daily intake of 1 mg/day (14.3 µg/kg/day) has been provisionally recommended (Aral and Vecchio-Sadus, 2008). Lithium salts (especially lithium carbonate) have been widely used as mood modifiers for human therapy, the central nervous system being the primary target for lithium toxicity. Daily intake of 167 mg lithium (i.e. 2.8 mg/kg/day for a 60 kg adult) is an established treatment regime in Sweden (Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals 131, 2002); reported therapeutic treatment regimes for treatment of mania with lithium salts have upper dosage limits of 340 mg Li+/day for acute mania (5.7 mg/kg/day) giving serum concentration up to 1.5 mM, and 170 – 227 mg Li+/day for prophylactic control (2.8 – 3.8 mg/kg/day) giving serum concentrations of 0.6 to 1.2 mM. Daily dosage required to maintain a serum level of 0.8 – 1.0 mM has been shown to range from 115 to 400 mg Li+ (1.9 – 6.7 mg/kg/day). The therapeutic window is narrow, with adverse symptoms reported at 1.5 mM (10.41 mg/l: Friedberg, Spyker, Herold 1991). Serum levels of 17.5 – 24.5 mg/l (2.5 – 3.5 mM) can cause moderate toxicity, with severe symptoms occurring at higher concentrations (Aral and Vecchio-Sadus, 2008). Clinically, haemodialysis is recommended for treatment of human overdose poisoning where lithium concentration exceeds 4 mM (27.8 mg/l) even in the absence of evident symptoms (Friedberg, Spyker, Herold 1991).

 

In mice, oral gavage with lithium carbonate (Li+ 18.7, 75, or 151 mg/kg/day) for 10 days produced serum lithium concentrations of 0.45, 1.25 or 4.26 mM (the highest dosage proving lethal for 2/3 mice). In another study, single oral administration of lithium chloride to pregnant mice at 65.5 mg Li+/kg/day gave rise to a maternal blood level of 1.8 mM lithium, with 5.7 µg Li/g in the embryo. Female rats fed 3.9 mg Li+/kg/day in diet have been reported to have plasma lithium concentrations of 0.5 – 0.63 mM (Moore et al, 1995).  Given this evidence that rats and mice require repeat-dose exposures to lithium comparable to or higher than those required in man to achieve comparable serum/plasma bone concentrations, it is appropriate to use human toxicity data for to establish effects of long-term, repeat exposure.

 

A detailed review of lithium toxicity (Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals 131, 2002) concluded that available data do not permit establishment of definitive NOAEL or LOAEL values. In animal tests, the kidney is a primary target organ for lithium toxicity. However the critical effect for occupational exposure to lithium (by inhalation) is irritation of the respiratory tract and this review described what was effectively a worst-case scenario for worker exposure: 1 mg Li/day (=14.3 µg/kg/day for a 70 kg worker) based on an 8h day worked in an atmosphere of 1 mg Li/cu.m (with 100% absorption from 10 cu.m inhaled air). At this level of exposure, systemic adverse effects were considered unlikely to occur. This is therefore considered to provide a conservative human NOAEL value for use in risk assessment.

 

Phosphate

Intake of inorganic phosphate is essential for maintenance of normal biological processes. Most phosphate uptake occurs via absorption of free orthophosphate: the extent and rate of absorption of other forms of phosphate is essentially dependent on their biotransformation to orthophosphates. Homeostatic regulation of phosphate in man and other animals allows them to tolerate considerable variations in phosphate intake; although continuous intake of phosphate at a high level may promote decalcification of bone, moderate doses have not been shown to impair uptake of calcium or other metal ions (including iron). The Maximum Tolerable Daily Intake level of phosphate for man has been set at 70 mg/kg/day as P (FAO/WHO/IPCS, 1982). This MTDI value has also been recognised by the European Food Safety Authority (EFSA, 2008b).

 

Rats fed a high orthophosphate diet (0.43% P content) for up to 150 days showed no evidence of physiological disturbance. In a separate study, rats fed diets containing 0.4 or 0.75% orthophosphoric acid over three generations (90 weeks) showed no adverse effects on growth, haematological parameters, reproduction or pathology; calcium metabolism also appeared unaffected, although dental attrition was somewhat more marked than in controls (FAO/WHO/IPCS, 1982). The 0.75% dietary administration in this study has been converted to an NOAEL value of 375 mg/kg/day, but it was concluded that establishment of an acceptable human intake level for phosphoric acid should not be based solely on such animal test data, since high level administration could lead to adverse changes in dietary mineral balance. An Acceptable Daily Intake of phosphorus (total, from foods and food additives) was therefore set at 30 mg/kg/day (unconditional acceptance) or up to 70 mg/kg/day (conditional acceptance) (FAO Nutrition Series No. 48A, 1970). This latter value corresponds to the MTDI cited earlier. Although limited, these findings raise no concerns regarding use of the European MTDI value for phosphate for the purpose of risk assessment.

 

Sodium monofluorophosphate

The European Food Safety Authority has reviewed the safety of this substance as a food additive. Noting that it is hydrolysed into fluoride and phosphate ions, EFSA concluded that inclusion in food up to a level giving a daily adult intake of 2 mg F- will not exceed the maximum tolerable daily intake of fluoride (and the associated intake of up to 8.8 mg phosphate causes no safety concern). However this level of fluoride intake by infants would be of concern (acceptable upper limit at 1 - 3 years = 1.5 mg/day) (EFSA 2008b).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Lithium hexafluorophosphate is reactive and unstable in water and air. Reaction in contact with water proceeds rapidly, with release of hydrogen fluoride (forming hydrofluoric acid). Such local generation of hydrogen fluoride/hydrofluoric acid at the site of contact with skin or other membranes, with consequent potential for serious local tissue damage, is a major cause of the observed corrosivity of the substance, and secondary tissue necrosis due to localised free fluoride ion concentrations is also a likely contributor to this. Ethical and practical reasons therefore make it inappropriate to conduct repeat-dose toxicity testing of lithium hexafluorophosphate in animals; since information is available on systemic toxicity of the ultimate hydrolysis products hydrogen fluoride, lithium/Li+, fluoride/F- and phosphoric acid/phosphate, such testing is also scientifically unnecessary. In accordance with Annex XI, 1.2 of the REACH Regulation testing is not scientifically necessary (see separate read-across justification document). On humane grounds, as indicated in article 15, 2 of Directive 2010/63/EU, such testing (expected to involve severe pain, suffering or distress likely to be long-lasting) should not be performed.

Repeat-dose toxicity data for the hydrolysis products clearly demonstrate that fluoride ions are the most toxic. In Europe a human tolerable maximum intake level of 7mgF-/day (100 microg/kg/day) has been set for adults. This corresponds to 133 microg LiPF6/kg/day.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Lithium hexafluorophosphate is reactive and unstable in water and air. Reaction in contact with water proceeds rapidly, with release of hydrogen fluoride (forming hydrofluoric acid). Such local generation of hydrogen fluoride/hydrofluoric acid at the site of contact with skin or other membranes, with consequent potential for serious local tissue damage, is a major cause of the observed corrosivity of the substance, and secondary tissue necrosis due to localised free fluoride ion concentrations is also a likely contributor to this. Ethical and practical reasons therefore make it inappropriate to conduct repeat-dose toxicity testing of lithium hexafluorophosphate in animals; since information is available on systemic toxicity of the ultimate hydrolysis products hydrogen fluoride, lithium/Li+, fluoride/F- and phosphoric acid/phosphate, such testing is also scientifically unnecessary. In accordance with Annex XI, 1.2 of the REACH Regulation testing is not scientifically necessary (see separate read-across justification document). On humane grounds, as indicated in article 15, 2 of Directive 2010/63/EU, such testing (expected to involve severe pain, suffering or distress likely to be long-lasting) should not be performed.

Oral route repeat-dose toxicity data for the hydrolysis products clearly demonstrate that fluoride ions are the most toxic: inhalation toxicity data are available for HF/F-, and fluoride ion absorption via the lungs is reported to be near-complete. An IOELV of 1.5 mg/cu.m (8h TWA for HF, as F-) has been set in Directive 2009/30/EC (following detailed consideration of the available data by the Scientific Committee on Occupational Exposure Limits). This corresponds to an LiPF6 concentration of 2.0 mg/cu.m.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Lithium hexafluorophosphate is reactive and unstable in water and air. It reacts rapidly with water, releasing hydrogen fluoride (forming hydrofluoric acid). Such local generation of hydrogen fluoride/hydrofluoric acid at the site of contact with skin or other membranes, with consequent potential for serious local tissue damage, is a major cause of the observed corrosivity of the substance, and secondary tissue necrosis due to localised free fluoride ion concentrations is also a likely contributor to this. Ethical and practical reasons therefore make it inappropriate to conduct repeat-dose toxicity testing of lithium hexafluorophosphate in animals; since information is available on systemic toxicity of the ultimate hydrolysis products hydrogen fluoride, lithium/Li+, fluoride/F- and phosphoric acid/phosphate, such testing is also scientifically unnecessary. In accordance with Annex XI, 1.2 of the REACH Regulation testing is not scientifically necessary (see separate read-across justification document). On humane grounds, as indicated in article 15, 2 of Directive 2010/63/EU, such testing (expected to involve severe pain, suffering or distress likely to be long-lasting) should not be performed.

Repeat-dose toxicity data for the hydrolysis products clearly demonstrate that fluoride ions are the most toxic. Following consideration of reported human volunteer trial results, the EU Risk Assessment Report on HF concluded that local irritation is likely to have occurred following repeated daily inhalation of HF at 0.74 mg/cu.m. This could be considered to correspond to 1.12 mg LiPF6/cu.m. However such a calculation is questionable, since:
- LiPF6 is a solid of relatively large particle size, which will not readily be suspended in the workplace atmosphere
- LiPF6 is itself corrosive and will form HF locally at the site of contact with moist membranes, local concentrations of HF might possibly reach irritant levels at an even lower concentration.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Lithium hexafluorophosphate is reactive and unstable in water and air. It reacts rapidly with water, releasing hydrogen fluoride (forming hydrofluoric acid). Such local generation of hydrogen fluoride/hydrofluoric acid at the site of contact with skin or other membranes, with consequent potential for serious local tissue damage, is a major cause of the observed corrosivity of the substance, and secondary tissue necrosis due to localised free fluoride ion concentrations is also a likely contributor to this. Ethical and practical reasons therefore make it inappropriate to conduct repeat-dose toxicity testing of lithium hexafluorophosphate in animals; since information is available on systemic toxicity of the ultimate hydrolysis products hydrogen fluoride, lithium/Li+, fluoride/F- and phosphoric acid/phosphate, such testing is also scientifically unnecessary. In accordance with Annex XI, 1.2 of the REACH Regulation testing is not scientifically necessary (see separate read-across justification document). On humane grounds, as indicated in article 15, 2 of Directive 2010/63/EU, such testing (expected to involve severe pain, suffering or distress likely to be long-lasting) should not be performed.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Lithium hexafluorophosphate is reactive and unstable in water and air. It reacts rapidly with water, releasing hydrogen fluoride (forming hydrofluoric acid). Such local generation of hydrogen fluoride/hydrofluoric acid at the site of contact with skin or other membranes, with consequent potential for serious local tissue damage, is a major cause of the observed corrosivity of the substance, and secondary tissue necrosis due to localised free fluoride ion concentrations is also a likely contributor to this. Ethical and practical reasons therefore make it inappropriate to conduct repeat-dose toxicity testing of lithium hexafluorophosphate in animals; since information is available on systemic toxicity of the ultimate hydrolysis products hydrogen fluoride, lithium/Li+, fluoride/F- and phosphoric acid/phosphate, such testing is also scientifically unnecessary. In accordance with Annex XI, 1.2 of the REACH Regulation testing is not scientifically necessary (see separate read-across justification document). On humane grounds, as indicated in article 15, 2 of Directive 2010/63/EU, such testing (expected to involve severe pain, suffering or distress likely to be long-lasting) should not be performed.
The substance is corrosive and skin contact will cause local skin corrosion.

Repeated dose toxicity: via oral route - systemic effects (target organ) other: bone

Repeated dose toxicity: inhalation - systemic effects (target organ) other: bone

Repeated dose toxicity: dermal - systemic effects (target organ) other: bone

Justification for classification or non-classification

It has been reported that long-term human exposure to fluoride (by inhalation, ingestion or skin contact) at a level above 100 µg/kg/day might lead to skeletal fluorosis, and at such exposure levels neurotoxicity and impaired thyroid function are also said to be possible. Chronic exposure by inhalation to lithium at a level above 14.3 µg/kg/day could cause respiratory tract irritation and long-term ingestion of more than 6.7 mg/kg/day (a reported maximal upper limit for long-term therapeutic use) could incur risks of adverse CNS effects and/or nephrotoxicity. Levels of LiPF6 exposure able to give rise to such fluoride or lithium doses are:

- 133 µg LiPF6/kg/day (= 100 µgF-/kg/day)

- 313 µg LiPF6/kg/day (= 14.3 µgLi+/kg/day) or 146.6 mg LiPF6/kg/day (= 6.7 mgLi+/kg/day).

On the basis of the known toxicity of fluoride, application of the classification STOT RE Cat. 1, H372

(bones, teeth; for labelling GHS08, Danger) under CLP regulation (1272/2008) is considered appropriate.