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Administrative data

Description of key information

The toxicity of sodium hydrogen difluoride will be dominated by local (site of contact) effects, as a consequence of its corrosive nature.  Systemic exposure is likely to be limited, but systemic toxicity is predicted to be due to fluoride and the critical effect will be skeletal fluorosis.  Comprehensive repeated dose oral toxicity data are available for sodium fluoride; read-across is therefore proposed. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: NTP study
Reason / purpose:
reference to same study
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: NTP protocol
Principles of method if other than guideline:
6-month study
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
Male and female rats were bred at the study laboratory. Breeder F344 rats (Harlan Industries, Indianapolis, IN) were placed on a low fluoride diet (<2.1 ppm fluoride) 1 month before monogamous pairing. Progeny that survived to weaning were distributed to weight classes and assigned to cages by a random number table. Rats were 5 to 6 weeks old when placed on study. Animals were houses five per cage with feed and water available ad libitum. Individual weights were recorded weekly throughout the studies. Water consumption was recorded daily by cage. The conditions the rats were kept in were; 22-24 degC, 40-60% humidity and 12 hours/day of fluorescent light.
Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
Groups of ten rats of each sex were administered 0, 10, 30, 100 or 300 ppm sodium fluoride in deionized water, available ad libitum for 6 months.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
No analytical verification of doses. The concentrations are nominal.
Duration of treatment / exposure:
The study was 6 months in length.
Frequency of treatment:
The sodium fluoride in water was available ad libitum.
Remarks:
Doses / Concentrations:
0, 10, 30, 100 or 300 ppm
Basis:
nominal in water
No. of animals per sex per dose:
10 animals per sex per dose
Control animals:
other: see details of study design
Details on study design:
Groups of ten rats of each sex were administered 0, 10, 30, 100 or 300 ppm sodium fluoride in deionized water, available ad libitum for 6 months. All test animals receiving water supplemented with sodium fluoride were provided with a low fluoride (<2.1 ppm) semisynthetic diet throughout the study. T The first two controls were only included in the female rat study.
Positive control:
Not applicable
Observations and examinations performed and frequency:
Rats were observed twice daily for mortality and morbidity, weighed initially, weekly and at termination. Clinical observations recorded daily. Food consumption recorded every other week for the first 13 weeks and for 1 week during each of the last 3 months. Water consumption was recorded daily.
Sacrifice and pathology:
Fluoride concentrations in bone, blood and urine were measured prior to necropsy. Necropsy was performed on all animals, with histopathological investigations at the two highest dose levels.
Other examinations:
No further observations
Statistics:
None reported
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
not examined
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY

No deaths occurred. From Week 6, chalky-white teeth with an unusual wear pattern were observed in rats at the high dose level. During the latter stages of the study, teeth were trimmed due to their unusual length; chipping was also observed.

BODY WEIGHT AND WEIGHT GAIN

Bodyweights and food consumption were lower at 300 ppm in both sexes


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)

Water consumption was slightly reduced at 300 ppm.


GROSS PATHOLOGY

Thickening of the gastric mucosa at 100 and 300 ppm.

HISTOPATHOLOGY

The principal effects were observed on the incisor teeth (300 ppm males) and stomach (both sexes at 100 and 300 ppm). In 300 ppm males, degeneration of the enamel organ was apparent. Gastric effects were characterised by a diffuse hyperplasia of the glandular mucosa .


OTHER FINDINGS
Dose descriptor:
NOEL
Effect level:
30 ppm
Sex:
male
Basis for effect level:
other: Gastric pathology
Dose descriptor:
NOEL
Effect level:
30 ppm
Sex:
female
Basis for effect level:
other: Gastric pathology
Dose descriptor:
NOAEL
Effect level:
100 ppm
Sex:
male
Basis for effect level:
other: Reduced bodyweight, food and water consumption; dental fluorosis
Dose descriptor:
NOAEL
Effect level:
100 ppm
Sex:
female
Basis for effect level:
other: Reduced bodyweight, food and water consumption; dental fluorosis
Critical effects observed:
not specified

Dose (ppm)

Survival

Mean Body Weight

Final Weight relative to control (%)

Initial

Final

Change

Male

Control

10/10

78 ±7

444 ±7

366 ±8

100

Control

10/10

78 ±7

450 ±7

372 ±10

101

Control

10/10

80 ±7

420 ±7*

339 ±8*

94

10

10/10

76 ±7

425 ±9

349 ±7

96

30

10/10

83 ±7

437 ±7

354 ±10

98

100

10/10

76 ±6

433 ±7

357 ±5

97

300

10/10

81 ±7

371 ±10**

290 ±8**

83

Female

Control

10/10

72 ±6

236 ±7

163 ±8

100

Control

10/10

67 ±6

234 ±4

167 ±6

99

10

10/10

75 ±7

232 ±3

156 ±6

98

30

10/10

69 ±7

234 ±6

166 ±7

99

100

10/10

69 ±7

235 ±4

166 ±8

100

300

10/10

70 ±7

212 ±3**

141 ±6

90

*Significantly different (P≤0.05) from the control group by Dunn’s or Shirley’s test

**P<0.01

Conclusions:
There were no deaths throughout these studies. The only observed effects were signs of dental fluorosis and thickening of the mucosa and ulcer formation in the glandular stomach at 100 and 300 ppm.
Executive summary:

Sodium fluoride was shown to have an effect on the teeth and stomach of rats in this study. There was no mortality; bodyweights, food consumption and water consumption were reuced at the highest dose level of 300 ppm. Signs of dental fluorosis were apparent in all animals at 300 ppm and microscopically in males at 300 ppm. Local irritant effects on the gastric mucosa (hyperplasia and ulceration) were noted at 100 ppm and 300 ppm, however this local effect is considered likely to be a consequence of the method of administration and is not relevant to the human risk assessment.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Study duration:
chronic
Species:
rat
Quality of whole database:
A number of high-quality repeated dose oral toxicity studies are available in the rat and mouse; studies were performed with the read-across substance sodium fluoride. As such, the studies demonstrate the systemic effects of fluoride exposure without the local effects of exposure to sodium hydrogen difluoride.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
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: Older, non-GLP published study.
Reason / purpose:
reference to same study
Reference:
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
Repeated exposure inhalation toxicity in rats
GLP compliance:
no
Remarks:
: older published study, pre-dates GLP
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
not specified
Sex:
female
Details on test animals and environmental conditions:
Female rats of various ages were used in this test. No environmental conditions are given.
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
Exposure of female rats of various age to 1 mg HF/m3 for 1 month, 6 hours per day.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
There was no analytical determination of concentration. The concentration stated is nominal.
Duration of treatment / exposure:
1 month
Frequency of treatment:
6 hours per day.
Remarks:
Doses / Concentrations:
1 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
The number of animals is not stated.
Control animals:
not specified
Details on study design:
Exposure of female rats of various age to 1 mg HF/m3 for 1 month, 6 hours per day.
Sacrifice and pathology:
Examination of the lungs,airways, bones and teeth at the end of the exposure.
Other examinations:
No further examination
Statistics:
None
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
Exposure of female rats of various age to 1 mg HF/m3 for 1 months, 6 hr/d resulted in damage to the dental enamel. This effect was especially seen in young animals and in animals of 17.6 to 18.6 months of age. The respiratory organs of the young animals showed atrophy and local oedema of the bronchial mucosa. In the older animals, the lungs showed peribronchial hyperplasia. In animals of about 12 months the formation of irregular shaped cavities in their bones
Dose descriptor:
LOAEC
Effect level:
1 mg/m³ air
Sex:
female
Basis for effect level:
other: Effects on the teeth, bones and respiratory tract were seen at the single concentration of HF investigated in this study.
Critical effects observed:
not specified

See above

Conclusions:
Exposure to HF vapour for one month resulted in effects on the teeth, bones and respiratory tract.
Executive summary:

Exposure of female rats of various ages to 1 mg HF/m3 for 1 months, 6 hr/d resulted in damage to the dental enamel. This effect was most marked in young animals and in animals of 17.6-18.6 months of age. The respiratory organs of the young animals showed atrophy and local oedema of the bronchial mucosa. In older animals, the lungs showed peribronchiqal hyperplasia. In animals of about 12 months old the formation of irregular shaped cavities in bones was noted.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
1 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
Older, non-standard study demonstrating systemic effects following inhalation exposure to HF.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
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: Older, non-GLP published study.
Reason / purpose:
reference to same study
Reference:
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
Repeated exposure inhalation toxicity in rats
GLP compliance:
no
Remarks:
: older published study, pre-dates GLP
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
not specified
Sex:
female
Details on test animals and environmental conditions:
Female rats of various ages were used in this test. No environmental conditions are given.
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
Exposure of female rats of various age to 1 mg HF/m3 for 1 month, 6 hours per day.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
There was no analytical determination of concentration. The concentration stated is nominal.
Duration of treatment / exposure:
1 month
Frequency of treatment:
6 hours per day.
Remarks:
Doses / Concentrations:
1 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
The number of animals is not stated.
Control animals:
not specified
Details on study design:
Exposure of female rats of various age to 1 mg HF/m3 for 1 month, 6 hours per day.
Sacrifice and pathology:
Examination of the lungs,airways, bones and teeth at the end of the exposure.
Other examinations:
No further examination
Statistics:
None
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
Exposure of female rats of various age to 1 mg HF/m3 for 1 months, 6 hr/d resulted in damage to the dental enamel. This effect was especially seen in young animals and in animals of 17.6 to 18.6 months of age. The respiratory organs of the young animals showed atrophy and local oedema of the bronchial mucosa. In the older animals, the lungs showed peribronchial hyperplasia. In animals of about 12 months the formation of irregular shaped cavities in their bones
Dose descriptor:
LOAEC
Effect level:
1 mg/m³ air
Sex:
female
Basis for effect level:
other: Effects on the teeth, bones and respiratory tract were seen at the single concentration of HF investigated in this study.
Critical effects observed:
not specified

See above

Conclusions:
Exposure to HF vapour for one month resulted in effects on the teeth, bones and respiratory tract.
Executive summary:

Exposure of female rats of various ages to 1 mg HF/m3 for 1 months, 6 hr/d resulted in damage to the dental enamel. This effect was most marked in young animals and in animals of 17.6-18.6 months of age. The respiratory organs of the young animals showed atrophy and local oedema of the bronchial mucosa. In older animals, the lungs showed peribronchiqal hyperplasia. In animals of about 12 months old the formation of irregular shaped cavities in bones was noted.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
1 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
Older, non-standard study demonstrating local effects following inhalation exposure to HF.

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Test material information:
Composition 1
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
No data are available.

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Test material information:
Composition 1
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
No data are available.

Mode of Action Analysis / Human Relevance Framework

Additional information

The substance will form HF under physiological conditions, with subsequent dissociation to the constituent (hydrogen, sodium and fluoride) ions. The substance is corrosive and, therefore, repeated inhalation and dermal exposure will result in local effects at the site of contact. The toxicologically relevant component of the substance is considered to be fluoride, and systemic toxicity following repeated oral and inhalation exposure may result from fluoride. Read-across is therefore proposed to other soluble fluoride salts, which demonstrate the critical effect to be skeletal fluorosis. Dermal absorption of fluoride is not predicted under normal conditions of use.

Repeated dose oral toxicity

No studies have been performed with sodium hydrogen difluoride, however comprehensive data are available for sodium fluoride. The repeated dose oral toxicity of sodium hydrogen difluoride and NaF are considered to be essentially identical, with the exception of likely irritant/corrosive effects of sodium hydrogen difluoride at high dose levels. The repeated dose oral toxicity of sodium hydrogen difluoride will be due to fluoride, therefore read-across from the comprehensive NTP dataset with the soluble salt NaF is appropriate.

In a 14-day range-finding study with NaF in the rat, mortality was seen at drinking water concentrations of 400 and 800 ppm. Signs of toxicity (reduced weight gain, reduced water consumption, lethargy and dehydration) were noted in surviving animals in these groups. The NOAEL for this study was 200 ppm.

In a 14-day range-finding study in the mouse, mortality was seen at the highest dose level of 800 ppm; signs of toxicity (reduced weight gain, abnormal gait and posture, reduced water consumption) were also apparent at this dose level. A NOAEL of 400 ppm is determined for this study.

In a 6-month rat study, the effects of exposure to NaF were limited to reduced weight gain, dental fluorosis, thickening and ulceration of the gastric mucosa at the highest dose level of 300 ppm; gastric effects were also seen at 100 ppm. The fluoride content of plasma, bone and teeth increased with dose levels. The NOEL for this study was 30 ppm, however these local effects are not considered to be relevant for the risk assessment therefore a NOAEL of 100 ppm can be determined.

In a 6 -month mouse study, mortality attributable to acute nephrosis was seen at the highest dose level of 600 ppm. Skeletal effects were seen in males at the lowest dose level of 50 ppm.

Repeated dose dermal toxicity

No studies are available. The effects of dermal exposure to sodium hydrogen difluoride will be dominated by local irritation / corrosion. There is unlikely to be significant dermal absorption of fluoride under normal exposure conditions, where the integrity of the skin barrier is maintained. Testing for repeated dose dermal toxicity can therefore be waived on scientific grounds and for reasons of animal welfare.

Repeated exposure inhalation toxicity

The effects of repeated inhalation exposure to sodium hydrogen difluoride may be local (due to the generation of HF) or systemic (due to the absorption of fluoride. However the substance is a non-volatile solid and significant inhalation exposure is not predicted based on its physicochemical properties. In a published study (Sadilova et al, 1974), female rats were exposed to 1 mg/m3 HF 6 hours/day for 1 month. Effects were noted on the teeth, bones and respiratory tract.

Summary

Effects of repeated fluoride exposure in experimental animals were seen on the teeth, bones, respiratory tract and kidney. Evidence from epidemiological studies in humans also indicate that prolonged exposure to fluoride causes dental and skeletal effects.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
This study is of high quality, of the longest duration and was performed in the preferred species.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Only one study is available.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Only one study is available.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
A waiver is proposed in accordance with column 2 of the Annex VIII and IX REACH data requirements (specific rules for adaptation from Column 1). The effects of dermal exposure will be dominated by local irritation / corrosion. There is no evidence of significant dermal absorption of sodium hydrogen difluoride under exposure conditions where the integrity of the skin barrier is maintained. Testing for repeated dose dermal toxicity can therefore be waived on scientific grounds and for reasons of animal welfare. The effects of repeated inhalation exposure to HF have been adequately characterised; the effects of repeated exposure to fluoride are also well characterised.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
A waiver is proposed in accordance with column 2 of the Annex VIII and IX REACH data requirements (specific rules for adaptation from Column 1). The effects of dermal exposure will be dominated by local irritation / corrosion. There is no evidence of significant dermal absorption of sodium hydrogen difluoride under exposure conditions where the integrity of the skin barrier is maintained. Testing for repeated dose dermal toxicity can therefore be waived on scientific grounds and for reasons of animal welfare. The effects of repeated inhalation exposure to HF have been adequately characterised; the effects of repeated exposure to fluoride are also well characterised.

Repeated dose toxicity: via oral route - systemic effects (target organ) other: bone

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: other

Justification for classification or non-classification

No classification is required for repeated dose toxicity according to CLP criteria.