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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study report published in a peer-reviewed journal. Unlike some other available studies, considered reliable for NOAEL determination in the HF EU RAR.
Justification for type of information:
Part of weight-of-evidence approach adapting the information requirements of Annex VIII 8.7.1, Annex XI 8.7.3 and Annex X 8.7.3 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 reprotoxicity testing of lithium hexafluorophosphate in animals and since information is available on the reprotoxicity 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 reprotoxicity (likely to involve severe pain, suffering or distress) should not be performed.

Data source

Reference
Reference Type:
publication
Title:
Multigenerational evaluation of sodium fluoride in rats
Author:
Collins T.F.X. et al
Year:
2001
Bibliographic source:
Food and Chemical Toxicology 39, 601-613

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
yes

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:
High purity (equal to USP reference sample).

Test animals

Species:
rat
Strain:
other: CD-BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
Bodyweight 51-75g at start of 1-week acclimatisation pre-study.
Fed on low-fluoride diet (F- 7.95 ppm)

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
other: water having <0.2 ppm F-
Details on mating procedure:
After 10 treatment weeks, mated 1:1 (if unmated, remated after 1 week).
Mating confirmation: sperm in vaginal lavage.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
F- by potentiometric titration.
Duration of treatment / exposure:
P generation: 10 weeks, then up to 3 mating weeks plus 21 postnatal days.
F1 generation: 10 weeks from postnatal day 21, then up to 3 mating weeks, plus 20 postnatal days.
F1 subset: dosing continued to postnatal day 90.
Frequency of treatment:
Continuous
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 25, 100, 175, 250 ppm
Basis:
nominal in water
No. of animals per sex per dose:
48M+48F/group
Control animals:
other: yes, <0.2 ppm in water
Details on study design:
P males: transferred to another (male fertility) study after mating.
P females: 8/48 terminated and examined at gestation day 20.
F1 pups: litter size controlled to 10 by postnatal day 4 cull.
F1 post-weaning: group sizes 36M+36F taken forward for mating, 10M+10F treated up to postnatal day 90.
Positive control:
No

Examinations

Parental animals: Observations and examinations:
Daily observations for toxic reaction during treatment.
Food and water consumption monitored.
At termination (10 rats/sex/group: P, F1 weanlings, F1 adults):
- gross lesions and organ weights recorded
- full tissue list subjected to histopathology examination (controls and 250 ppm groups)
- less complete tissue list subjected to histopathology examination (other groups).
Litter observations:
F1 pups: observations including sexing and weighing on postnatal days 0,4,7,14,21
Postmortem examinations (parental animals):
Gross abnormalities, organ weights.
Postmortem examinations (offspring):
Gross abnormalities, organ weights.
Statistics:
Fisher's exact, ANOVA, ANCOVA, LSD tests applied to appropriate parameters.
Reproductive indices:
Females:
Mating index (sperm-positive/placed for mating, %).
Fertility index 1 (littering/sperm-positive, %).
Fertility index 2 (littering/placed for mating, %).
Time to mating.

Males:
Mating index (giving sperm-positive females/placed for mating, %).
Fertility index 1 (producing litter/giving sperm positive females, %).
Fertility index 2 (producing litter/placed for mating, %).
Offspring viability indices:
F1 progeny numbers recorded:
- implants
- total born and born alive
- alive on day 4 (pre-cull)
- post-cull survivors on days 4, 7, 14 and 21.

F1 bodyweights recorded:
- on days 0 and 4
- post-cull on days 4, 7, 14, and 21.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Reduced food consumption and weight gain in P males at 250 ppm only.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Reduced food consumption and weight gain in P males at 250 ppm only.
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Growth lines in teeth at 250 ppm. Occasional stomach ridge hyperkeratosis in a few P and F1 rats (considered a response to NaF).No other differences between test and control animals, in reproductive or other organs/tissues.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Test substance intake: Calculated fluoride intakes: P males, 10.5 mgF-/kg/day; P females, 12.3 mgF-/kg/day. F1 males, 10.9 mgF-/kg/day; F1 females, 12.7 mgF-/kg/day.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
Mating indices (>90%) unaffected by treatment. Male and female reproduction indices did not differ significantly between test groups and controls.

Details on results (P0)

No evidence of reproductive toxicity.

Effect levels (P0)

Dose descriptor:
NOEL
Remarks:
for sodium fluoride in drinking water
Effect level:
250 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on calculated intake, 250 ppm NaF was equivalent to 28.4 mg NaF/kg/day or 12.8 mgF-/kg/day. No adverse effects on reproduction. No effect on bodyweight-relative organ weights or brainweight-relative organ weights.

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

No evidence of toxicity to reproduction.

Effect levels (F1)

Dose descriptor:
NOEL
Remarks:
Sodium fluoride in drinking water
Generation:
F1
Effect level:
250 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on calculated intake, 250 ppm NaF was equivalent to 28.4 mg NaF/kg/day or 12.8 mgF-/kg/day. No adverse effects on reproduction. No effect on bodyweight-relative organ weights or brainweight-relative organ weights.

Results: F2 generation

Effect levels (F2)

Dose descriptor:
NOEL
Remarks:
Sodium fluoride in drinking water
Generation:
F2
Effect level:
250 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on calculated intake, 250 ppm NaF was equivalent to 28.4 mg NaF/kg/day or 12.8 mgF-/kg/day. No adverse effects on reproduction. No effect on bodyweight-relative organ weights or brainweight-relative organ weights.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Administration of fluoride in drinking water, at levels up to a calculated intake of 12.8 mg F-/kg/day, had no adverse effect on reproduction and produced no significant systemic toxicity in rats.