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Administrative data

Key value for chemical safety assessment

Genetic toxicity in vivo

Description of key information
Studies in vitro and in vivo are available for sodium fluoride and hydrogen fluoride.
Link to relevant study records
Reference
Endpoint:
in vivo mammalian germ cell study: cytogenicity / chromosome aberration
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published study
Reason / purpose:
reference to same study
Reference:
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was performed in the mouse and investigated the incidence of chromosomal aberrations in bone marrow cells and the incidence of micronuclei in erythrocytes.
GLP compliance:
not specified
Type of assay:
other: combined chromosomal aberration and micronucleus assay
Test material information:
Composition 1
Species:
mouse
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
No further information given.
Route of administration:
oral: drinking water
Vehicle:
The test substance was administered in the water.
Details on exposure:
The cytogenetic effects of sodium fluoride (NaF) were measured in mice following administration in the drinking water for 6 weeks.
Duration of treatment / exposure:
Sodium fluoride was administered in the drinking water for 6 weeks.
Frequency of treatment:
Sodium fluoride, administered in the drinking water was available ad libitum for 6 weeks.
Post exposure period:
No post exposure period.
Remarks:
Doses / Concentrations:
200, 400 mg/L
Basis:
nominal in water
Control animals:
yes, concurrent no treatment
Positive control(s):
A concurrent postive control was used.
Tissues and cell types examined:
Micronuclei were measured in peripheral blood erythrocytes following 1 and 6 weeks of administration. Bone marrow cell preparations were examined for the presence of chromosome aberrations following 6 weeks of treatment.
Details of tissue and slide preparation:
Micronuclei were measured in peripheral blood erythrocytes following 1 and 6 weeks of NaF administration. Bone marrow cell preparations were examined for the presence of chromosome aberrations following 6 weeks of treatment; metaphase and anaphase cells were examined. Anaphase cells were scored in three independent laboratories, two of which also scored metaphase cells from the same slides.
Evaluation criteria:
No evaluation criteria.
Statistics:
Not relevant
Sex:
male/female
Genotoxicity:
negative
Remarks:
No evidence of micronuclei in erythrocytes or cheomosomal aberrations in bone marrow cells.
Toxicity:
yes
Remarks:
Mortality at 400 mg/L; bodywieght effects at 200 and 400 mg/L
Vehicle controls valid:
yes
Negative controls valid:
not applicable
Positive controls valid:
yes
Additional information on results:
Bone fluoride levels were determined and showed a dose-related incorporation of fluoride. No increases in micronuclei were seen in peripheral erythrocytes at either time point, and no increases in chromosome aberrations were seen in bone marrow cells when metaphase or anaphase cells were examined.

Bone fluoride levels were determined and showed a dose-related incorporation of fluoride. No increases in micronuclei were seen in peripheral erythrocytes at either time point, and no increases in chromosome aberrations were seen in bone marrow cells when metaphase or anaphase cells were examined. A concurrent positive control, cyclophosphamide, produced significant increases in peripheral blood cell micronuclei and in chromosome aberrations in bone marrow cells in metaphase. No increases in aberrations were seen in the same cyclophosphamide-treated mice when anaphase cells were examined.

Conclusions:
Interpretation of results (migrated information): negative
Sodium fluoride did not cause any cytogenetic effects in mice under the conditions of this study
Executive summary:

The potential for sodium fluoride to cause chromosomal effects was investigated in a drinking-water study in mice. Mice were exposed for 1 or 6 weeks to sdoium fluoride. No evidence of micronuclei formation was seen in peripheral blood erythrocytes afer 1 or 6 weeks; no evidence of chromosomal aberration was seen in bone marrow cells after exposure for 6 weeks. Marked toxicity (including mortality) was seen at the highest dose level in this study.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vivo:

Overview

Under physiological conditions, the substance will dissociate to form its constituent ions (i.e. sodium, hydrogen and fluoride). The hydrogen and sodium ions exist in the body at high levels and are therefore unlikely to be genotoxic. Genotoxicity data for fluoride substances are available and are referenced.

Genetic toxicity in vitro (fluoride)

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 lymphoma assay (NTP, 1990). Sister chromatid exchange and chromosomal aberrations are reported in an additional NTP study. Caspary et al (1987) report positive results for sodium fluoride and sodium hydrogen fluoride at cytotoxic concentrations in a mouse lymphoma assay.

Genetic toxicity in vivo (fluoride)

Gerdes (1971) reports a marginally (but not statistically significant) positive response in a study in Drosophila melanogaster; positive effects in Drosophila are also reported by Mohamed et al (1971). The significance of these results is unclear; the EU RAR for HF considers the findings of these two Drosophila studies to be inconclusive. 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. In contrast, a poorly reported inhalation exposure study performed with HF (Voroshilin et al, 1975) reports clastogenicity in the bone marrow of exposed rats but no dominant lethal effect in exposed mice.

Conclusion on the genotoxicity of fluoride

The EU RAR for HF 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 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).


Justification for selection of genetic toxicity endpoint
Studies with HF and NaF are available. Negative results are shown for bacterial and mammalian cell mutation, however a positive result is shown for clastogenicity in vitro. A negative result is shown in a high quality mouse micronucleus/cytogenicity assay in vivo; this is therefore selected.

Justification for classification or non-classification

No classification is proposed. The available data indicate 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). Data therefore indicate that the substance is unlikely to be genotoxic.