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Toxicological information

Repeated dose toxicity: oral

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Administrative data

repeated dose toxicity: oral, other
other: review of effects of chronic exposure of human population
Type of information:
other: Information on major hydrolysis product of the registered substance (released rapidly on contact with water/moisture).
Adequacy of study:
weight of evidence
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Expert committee review including assessment of fluoride toxicity.
Justification for type of information:
Part of weight-of-evidence approach adapting the information requirements of Annex VIII 8.6.1 and Annex IX 8.6.2 under REACH in accordance with Annex XI Section 1.2. 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: delayed onset of deep tissue damage and pain is known after skin contact with HF solutions below 20% in concentration. 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, and 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.

Data source

Reference Type:
review article or handbook
Fluoride in Drinking Water: A Scientific Review of EPA's Standards
Committee on Fluoride in Drinking Water, National Research Council
Bibliographic source:
National Academies Press, Washington ISBN: 0-309-65796-2

Materials and methods

Principles of method if other than guideline:
Expert review of fluoride intake and effects on human health.

Test material

Constituent 1
Reference substance name:
Hydrogen fluoride
EC Number:
EC Name:
Hydrogen fluoride
Cas Number:
Details on test material:
Inorganic fluoride in drinking water.
Fluoride is a hydrolysis product of the reaction of LiPF6 with water.

Test animals

other: Humans

Administration / exposure

Details on oral exposure:
Intake in drinking water.

Results and discussion

Results of examinations

Details on results:
Total inorganic fluoride intake in the USA, 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.

Effect levels

Remarks on result:
other: Not determined
see "any other information on results" for details

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Identified human health effects of excess fluoride intake include fluorosis of the dental enamel: severe fluorosis affects about 10% of children in US communities drinking water containing fluoride at or close to 4 mg/l. Skeletal fluorosis and increased propensity to bone fracture may also be increased in populations drinking water with 4 mg fluoride/l, but the data on these endpoints was considered uncertain.

Applicant's summary and conclusion

Fluoride intake in drinking water at levels close to or above 4 mg/l is associated with dental fluorosis and perhaps also bone fluorosis and/or weakening.