Lithium hexafluorophosphate(1-)

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

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: Well described report of a scientifically robust 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 8.7.2 and Annex X 8.7.2 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:

Developmental toxicity of sodium fluoride measured during multiple generations

Author:

Collins T.F.X. et al

Year:

2001

Bibliographic source:

Food and Chemical Toxicology 39, 867–876

Materials and methods

Principles of method if other than guideline:

Examination of a subset of F0 females and their litters (F1) from each study group of a 2-generation reproduction study were examined: implant status, foetal weight, length and sex plus morphology were recorded. A subset of F1 females and their litters were later similarly examined, with soft-tissue and skeletal development of F2 foetuses being recorded.

GLP compliance:

yes

Test material

Test material information

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:

Purity equal to that of a USP reference sample.
Sodium fluoride is a soluble salt, dissociating readily in water to release F-.

Test animals

Species:

rat

Strain:

other: CD

Details on test animals or test system and environmental conditions:

51-75g bodyweight on receipt in test laboratory. Fed on low-fluoride diet (F- 7.95 ppm).

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

other: purified water, fluoride <0.2 ppm

Details on exposure:

Continuous, via drinking water.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

F- by potentiometric titration.

Details on mating procedure:

After 10 weeks, mated 1:1 (if unmated, remate after 1 week)

Duration of treatment / exposure:

P generation: 10 weeks then up to 3 mating weeks + 20 days of gestation.
F1 generation: continuous until gestation day 20.

Frequency of treatment:

Continuous

Duration of test:

As details for treatement duration.

No. of animals per sex per dose:

P females: 8/group.
F1 females: 36/group.

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

Clinical signs, macroscopic abnormalities at necropsy.

Ovaries and uterine content:

Corpora lutea, resorption sites, implants, early and late deaths.

Fetal examinations:

Sexed, measured, examined for abnormalities. F2 foetuses only: separately fixed and examined for skeletal and soft-tissue abnormalities .

Statistics:

ANOVA, ANCOVA, LSD test as appropriate.

Indices:

Implantation efficiency, % early + late deaths/litter, litters with runts, viable foetuses, foetal bodyweights

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
No definitive evidence of maternal toxicity was seen: although F0 female weight gains were reduced at the two highest exposure levels (175 and 250 ppm NaF), this was seen only at 175 ppm and not at 250 ppm in F1 females. No effect of treatment on reproductive performance.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

12.7 other: mgF-/kg/day

Based on:

other: 250 ppm NaF in drinking water

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

12.7 other: mgF-/kg/day

Based on:

other: 250 ppm NaF in drinking water

Basis for effect level:

other: F1

3

Dose descriptor:

LOAEL

Effect level:

12.7 other: mgF-/kg/day

Based on:

other: 250 ppm NaF in drinking water

Basis for effect level:

other: other:

4

Dose descriptor:

NOAEL

Effect level:

8.5 other: mgF-/kg/day

Based on:

other: 175 ppm NaF in drinking water

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects. Remark: no evidence of teratogenic activity

Details on embryotoxic / teratogenic effects:
Corpora lutea, implants, viable foetuses, % early and late deaths/litter all unaffected by treatement. No significant effect on foetal bodyweights.
Decreased ossification of the hyoid bone recorded, significant only in F2 foetuses of the 250 mg NaF/l group and when analysed on a total pups (not per litter) basis. No other treatment-related skeletal effects were seen.
No effect of treatment on visceral development in foetuses.

Effect levels (fetuses)

Dose descriptor:

LOAEL

Effect level:

12.7 other: mgF-/kg/day

Based on:

other: 250 ppm NaF in drinking water

Sex:

not specified

Remarks on result:

not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Water intake was affected by reduced palatability at higher test concentrations.

Calculated F- intakes:

- 1.5 mg/kg/day from 25 ppm NaF

- 5.6 mg/kg/day from 100 ppm NaF

- 8.5 mg/kg/day from 175 ppm NaF

- 12.7 mg/kg/day from 250 ppm NaF.

Applicant's summary and conclusion

Conclusions:

No evidence of teratogenic activity; decreased hyoid bone ossification significant only at the highest tested concentration.