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Toxicological information

Repeated dose toxicity: oral

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Administrative data

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
Cross-reference
Reason / purpose:
reference to same 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:
other: NTP protocol
Principles of method if other than guideline:
6-month study
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Sodium fluoride

Test animals

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.

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. T 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

open allclose all
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

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 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.