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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: Range-finding study for the NTP carcinogenicity study.

Data source

Reference
Reference Type:
publication
Title:
Technical Report on the Toxicology and Carcinogenesis Studies of Sodium Fluoride in F344/N Rats and B6C3F1 Mice.
Author:
NTP
Year:
1990
Bibliographic source:
U.S Department of Health and Human Services. NTP TR 393, NIH Publication No. 91-2848

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: NTP protocol
Principles of method if other than guideline:
14-day dose range-finding study in the rat.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Sodium fluoride (read-across)

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
Male and female rats were obtained from Charles River Laboratories (Portage, MI) and were observed for 6 days. The rats were 5 weeks old when placed on the study. The rats were fed on a semisynthetic low fluoride diet, available ad libitum. Water was supplied in glass bottles with rubber stoppers and stainless steel sipper tubes that were chnaged every 3 days. The cages were kept at a temperature of 21-23 degC with a relavtive humidity of 40-60%. Fluorescent light was supplied for 12 hours per day.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
0, 50, 100, 200, 400 or 800 ppm sodium fluoride in deionised water, available ad libitum.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Nominal concentrations.
Duration of treatment / exposure:
The study was 14 days in length. The sodium fluoride was available ad libitum in the drinking water.
Frequency of treatment:
The sodium fluoride was available ad libitum in the drinking water.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 100, 200, 400 or 800 ppm
Basis:
nominal in water
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
yes
Details on study design:
Groups of five rats of each sex received 0, 50, 100, 200, 400 or 800 ppm sodium fluoride in deionised water ad libitum. Animals were housed five per cage with semisynthetic low fluoride feed available ad libitum. Water consumption was recorded every 3 days. The rats were observed twice daily for signs of morbidity, mortality and signs of toxicity. They were weighed at the beginning, at the end of the first week and at necropsy. All animals were necropsied and tissues examined for gross lesions. No further investigations were performed.
Positive control:
Not relevant

Examinations

Observations and examinations performed and frequency:
Water consumption was recorded every 3 days. The rats were observed twice daily for signs of morbidity, mortality and signs of toxicity. They were weighed at the beginning, at the end of the first week and at necropsy.
Sacrifice and pathology:
All animals were necropsied and tissues examined for gross lesions.
Other examinations:
No further examinations
Statistics:
Various

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):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
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:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
All male and female rats given water containing 800 ppm sodium fluoride died; 1/5 female given 400 ppm also died. No gross lesions were observed at necropsy. All groups of males and females surviving to the end of the studies gained weight except the group receiving 400 ppm. In this group, 4/5 male lost 5-31% of their initial body weight and 3/4 female lost 10-29% of their initial body weight.

The following signs of toxicity were noted in all animals in the two highest dose groups: dehydration and lethargy by day 4 and hunched posture by day 5. In addition, reduced water consumption recorded by cage for male and female in the second highest dose group (400 ppm).

Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
200 ppm
Sex:
female
Basis for effect level:
other: Mortality, bodyweight effects, clinical signs, reduced water consumption
Dose descriptor:
NOEL
Effect level:
200 ppm
Sex:
male
Basis for effect level:
other: Bodyweight effects, clinical signs, reduced water consumption

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

5/5

86 ±5

167 ±6

81 ±3

100

50

5/5

79 ±3

151 ±4

72 ±2

91

100

5/5

75 ±4

146 ±5*

71 ±1*

88

200

5/5

77 ±3

140 ±6**

62 ±4**

84

400

5/5

80 ±3

69 ±6**

-11 ±5**

41

800

0/5

79 ±2

-

-

-

Female

Control

5/5

80 ±4

133 ±2

53 ±3

100

50

5/5

74 ±3

128 ±3

53 ±4

96

100

5/5

79 ±4

128 ±2

49 ±2

96

200

5/5

77.0 ±5

128 ±4

51 ±3

96

400

4/5

80 ±4

79 ±14**

0 ±15**

59

800

0/5

77 ±3

-

-

-

*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:
In the 14 day study, all male and female rats given water containing 800 ppm of sodium fluoride died. Effects at the second highest concentration (400 ppm) included weight loss, dehydration and lethargy. All other groups showed little signs of toxicity; males and females surviving to the end of the study gained weight.
Executive summary:

In the 14 day study, all male and female rats given water containing 800 ppm of sodium fluoride died; 1/5 female given 400 ppm died. No gross lesions were observed at necropsy. All groups, male and female, surviving to the end of the studies gained weight except the group receiving 400 ppm. In this group, 4/5 male lost form 5-31% of their initial body weight and 3/4 female lost from 10-29% of their initial body weight. The following signs of toxicity were noted in all animals in the two highest dose groups: dehydration and lethargy by day 4 and hunched posture by day 5. In addition, reduced water consumption was seen at 400 ppm.