Hydrogen fluoride

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: NTP study

Data source

Reference

Reference Type:

publication

Title:

Technical Report on the Toxicology and Carcinogenesis Studies of Sodium Fluoride in F344/N Rats and B6C3F Mice.

Author:

NTP

Year:

1990

Bibliographic source:

U.S Department of Health and Human Services. NTP TR 393, NIH Publication No. 91-2848, December 1990

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: NTP protocol

Principles of method if other than guideline:

6-month study

GLP compliance:

not specified

Limit test:

no

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

Molecular formula:

NaF

IUPAC Name:

sodium fluoride

Details on test material:

Sodium fluoride

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system 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.

Administration / exposure

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.

Doses / concentrations

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. The first two controls were only included in the female rat study.

Positive control:

Not applicable

Examinations

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

Results and discussion

Results of examinations

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

Effect levels

1

Dose descriptor:

NOEL

Effect level:

30 ppm

Sex:

male

Basis for effect level:

other: Gastric pathology

2

Dose descriptor:

NOEL

Effect level:

30 ppm

Sex:

female

Basis for effect level:

other: Gastric pathology

3

Dose descriptor:

NOAEL

Effect level:

100 ppm

Sex:

male

Basis for effect level:

other: Reduced bodyweight, food and water consumption; dental fluorosis

4

Dose descriptor:

NOAEL

Effect level:

100 ppm

Sex:

female

Basis for effect level:

other: Reduced bodyweight, food and water consumption; dental fluorosis

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

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

Applicant's summary and conclusion

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 reduced 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.