Registration Dossier

Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: chromosome aberration
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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well designed in vivo study published in a peer-reviewed journal.
Justification for type of information:
Part of weight-of-evidence approach adapting the information requirements of Annex IX 8.4 under REACH in accordance with Annex XI Section 1.2. 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 consider genotoxicity testing of lithium hexafluorophosphate in animals and since information is available on the genotoxicity of the hydrolysis products hydrogen fluoride, lithium fluoride and phosphoric acid, this is also scientifically unnecessary (see separate read-across justification in Section 13). In accordance with Annex XI, 1.2 of the REACH Regulation testing is not scientifically necessary based on weight-of evidence approach. On humane grounds, as indicated in Article 15, 2 of Directive 2010/63/EU, animal testing for genotoxicity (likely to involve severe pain, suffering or distress) should not be performed.

Data source

Reference
Reference Type:
publication
Title:
Sodium fluoride and chromosome damage (in vitro human lymphocyte and in vivo micronucleus assays)
Author:
Albanese R.
Year:
1987
Bibliographic source:
Mutagenesis vol.2 no.6 pp.497-499

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Principles of method if other than guideline:
Rats dosed orally, bone marrow erythrocytes scored for micronuclei.
GLP compliance:
not specified
Type of assay:
micronucleus assay

Test material

Constituent 1
Reference substance name:
Sodium fluoride
EC Number:
231-667-8
EC Name:
Sodium fluoride
Cas Number:
7681-49-4
IUPAC Name:
sodium fluoride
Details on test material:
Analar quality NaF.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
90-140g bodyweight

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
Distilled water
Details on exposure:
Single oral dose
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
500 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
5 for each sampling time
Control animals:
yes
Positive control(s):
Cyclophosphamide

Examinations

Tissues and cell types examined:
Bone marrow cells
Details of tissue and slide preparation:
Paintbrush smears
Evaluation criteria:
Micronucleated cells recorded in 2000 polychromatic erythrocytes (PEs)
Normochromatic erythrocytes (NEs) in 1000 PEs recorded.

Results and discussion

Test results
Sex:
male
Genotoxicity:
negative
Toxicity:
yes
Remarks:
4/5 rats dosed at 1000 mg/kg died before the 48h sampling time
Vehicle controls validity:
valid
Positive controls validity:
valid
Additional information on results:
NE/PE ratio was close to 1 in vehicle control and NaF treated groups, giving no indication of bone marrow toxicity.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
No evidence of chromosome-damaging activity was detected in this in vivo study.