Registration Dossier

Registration Dossier

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Administrative data

Description of key information

Barium fluoride will dissociate under physiological conditions to form barium and fluoride ions. Since no data on the repeated dose toxicity are available for barium fluoride, the available studies with sodium fluoride and barium chloride were used to assess the toxicity of Ba2+ and F- ions. The calculated oral NOAEL of barium fluoride based on the NOAEL of fluoride (7.4 mg/kg bw/day) is lower than the calculated NOAEL of barium fluoride based on the NOAEL of barium (78 mg/kg bw/day) therefore it is concluded that the critical systemic toxic effects of barium fluoride after repeated exposure will be due to fluoride.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Test procedure in accordance with generally accepted scientific standard and described in sufficient detail. Data and rating according to the SIDS 2005 on barium carbonate.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Barium chloride dihydrate (BaCl2 * 2H2O) was given for 92 days to Fischer 344/N rats in their drinking water at levels of 0, 125, 500, 1000, 2000 and 4000 ppm.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Simonsen Laboratories (Gilroy, CA)
- Age at study initiation: 32 days
- Housing: The animals were housed five per cage in drawer type polycarbonate cages. The shelves supporting the cages were covered with filter sheets. The bedding was (Ab-Sorb-Dri, Lab Products, Rochelle Park, NJ)
- Diet (ad libitum): NIH-07 pellets (Ziegler Brothers, Gardners, PA)
- Water (ad libitum): dosed with test substance or undosed water
-Quarantine period: 10 to 11 days after arrival, and representatives were necropsied to verify that they were grossly free of disease.

ENVIRONMENTAL CONDITIONS
- Temperature: 21 to 24 °C
- Air changes (per hr): Filtered fresh air (13.5 room vol/hr) was supplied directly and removed from the animal room.
- Photoperiod (hrs dark / hrs light): 12/12
No further information on the test animals was stated.
Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:Solutions were made weekly in 19-liter quanities by dissolving weighed portions of the chemical in glass-distilled water.
No further information on details on oral exposure was stated.


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dosage analyses were performed on all levels before and after use, and at the beginning and midway through the test period, indicated that the concentrations were within 1 to 6 % of the theroretical concentrations.
Duration of treatment / exposure:
92 consecutive days
Frequency of treatment:
Dosed water on an ad libitum basis during treatment.
Remarks:
Doses / Concentrations:
4000 ppm BaCl2 * 2H20
Basis:
nominal in water
Remarks:
Doses / Concentrations:
2000 ppm BaCl2 * 2H20
Basis:
nominal in water
Remarks:
Doses / Concentrations:
1000 ppm BaCl2 * 2H20
Basis:
nominal in water
Remarks:
Doses / Concentrations:
500 ppm BaCl2 * 2H20
Basis:
nominal in water
Remarks:
Doses / Concentrations:
125 ppm BaCl2 * 2H20
Basis:
nominal in water
No. of animals per sex per dose:
Groups of 10 per dose level after weight-sorting them by sex.
Control animals:
yes, concurrent vehicle
Positive control:
No data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- twice daily for clinical signs

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

WATER CONSUMPTION (if drinking water study): Yes
- Time schedule for examinations: twice weekly

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: no data
- Animals fasted: No data
- How many animals: 7-10 animals
- Parameters checked in table: serum sodium potassium, calcium, phosphorus

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: on each animal at 0, 45 to 48, and 91 days of exposure
- Dose groups that were examined: all
- Battery of functions tested: undifferentiated motor activity, forelimb and hindlimp grip strengths, thermal sensitivity to a 55°C water bath, startle response to acoustic and air-puff stimuli, and hindlimb foot splay.

DETAILED CLINICAL OBSERVATIONS: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

URINALYSIS: No data

No further information on observations and examinations performed and frequency was stated.



Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All animals were examined for gross lesions. The brain, liver, right kidney, lung, thymus, right testis, heart, and adrenals were weighed before fixation
HISTOPATHOLOGY: Yes
Complete histologic exams were performed on 30 or more tissues from animals of 4000 ppm and the control groups. Because histopathological changes were observed in several tissues (thymus, spleen, kidneys, and lymph nodes) from rats in the 4000 ppm group, these tissues were examined from the lower dose animals to determine a no-effect level.
No further information on sacrifice and pathology were stated.
Other examinations:
none
Statistics:
Each parameter for which individual values were available was subjected to a linaer lesat squares regression over the dose levels and the direction of the slope and the p value indicating the significance of the deviation of the slope from 0 was determined. Group means and standard deviation or standard errors were calcualted for continuous variables. the multiple comparison procedure of Dunnett (1955) was employed for pairwise comparisons of these variables between dosed groups and controls. Fisher's exact test was used to make pairwise comparisons of discrete variables between dosed groups and controls and the Cochran-Armitage test was used to assess the significance of dose-related trends (Armitage, 1971; Gart et al., 1979). Temporal and dose-related variations were evaluated using a repeated measures analysis of variance (Winter, 1971). When a collection of measurements were made on each animal, a multivariate analysis of variance (Morrison, 1976) was used to test for the simultaneous equality of measurements across dose levels.
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 specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
Three of 10 male and 1 of 10 female rats in the 4000 ppm groups died during the last week of the study. No clinical signs were oberved.

BODY WEIGHT AND WEIGHT GAIN
Body weights of both sexes in the 4000 ppm groups were significantly (p< 0.05) lower than the controls. Signs of weight loss were observed.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Rats in the 4000 ppm groups consumed 70 % of water consumed by controls. It is not clear whether the effcets are toxicity related or due to palatobility

CLINICAL CHEMISTRY
In the male rats, there was a significant elevation in phosphorous in the 1000, 2000, and 4000 ppm groups compared with the controls. In the female rats, a significant elevation in phosphorous was seen in the 500, 1000, 2000, and 4000 ppm groups. The biological significance of the changes in females are regarded as marginal due to lower than expected control values.

ORGAN WEIGHTS
The liver weights of the rats received 4000 ppm were depressed. The absolute kidney weights were elevated in the 1000 and 4000 ppm females, and the relative kidney weights were elevated in 4000 ppm to males and 1000 ppm or greater to females. These changes were variable and were probably related to treatment-depressed body weights rather than kidney toxicity. Tymus weights were depressed in the high dose female rats.

GROSS PATHOLOGY/HISTOPATHOLOGY
The kidney changes in rats were limited to few foci of dilated tubules in the outer medulla or meduallary rays. Tubular cell regression, casts, and crystals were not a feature of the renal lesions in rats. Lymphoid depletion was also present in the spleen and thymus of the early death rats.
There were no treatment-related histopathologic effects in the brain or other tissues of rats.

NEUROBEHAVIOUR
Compared to their controls, rats exposed to 2000 ppm BaCl2 or lower did not show any consistent changes in behavoioural indices (motor activity, fore- and hindlimp grip strength, and thermal sensitivity). Marginal although significant behavioural effects were noted at the 4000 ppm level in rats. these changes were probably a result of the overall BaCl2 toxicity observed at the 4000 ppm dose level.The behavioural effects observed at the 4000 ppm are as follows: Decreased undifferentiated motor acivity in female rats on day 91. No significant or dose-related effects were seen in the startle response to acoustic and air-puff stimuli or the hindlimb foot splay.
Dose descriptor:
NOAEL
Effect level:
2 000 ppm
Sex:
male/female
Basis for effect level:
other: see remark
Dose descriptor:
NOAEL
Effect level:
80.9 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: calculated as Ba2+
Dose descriptor:
NOAEL
Effect level:
61.1 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: calculated as Ba2+
Critical effects observed:
not specified
Conclusions:
The NOAEL of Barium chloride is 2000 ppm (corresponding to 61.1 and 80.9 mg Ba/kg bw/day for male and female rats respectively)
Executive summary:

Barium chloride dihydrate was administered for 92 days to Fischer 344/N rats in drinking water at levels of 0, 125, 500, 1000, 2000, and 4000 ppm. Mortality was observed in 3/10 males and 1/10 females in the 4000 ppm group. Depressed body weight gains, elevated phosphorus levels and chemically related lesions in the kidney and lympoid tissue at the highest dose level of 4000 pm. At 4000 ppm, motor activity, grip strength, and thermal sensitivity were marginally affected. These effects were probably secondary changes resulting from barium chloride toxicity observed at this dose level. Individual effects observed at 2000 ppm barium chloride in drinking water (corresponding to the final barium dose of 61.1 and 80.9 mg Ba/kg bw/day to male and female rats respectively) were regarded as not treatment-related and this dose levels represents the NOAEL.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: High quality range-finding study for the NTP carcinogenicity study.
Qualifier:
according to guideline
Guideline:
other: NTP protocol
Principles of method if other than guideline:
6-month repeated dose study.
GLP compliance:
not specified
Limit test:
no
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
Progeny of C57BL/N6 female and C3H/HeN male mice, obtained from Charles River Laboratories, Wilmington, DE, were used in this study. Mice were 4 to 6 weeks old when placed on study. Their diet consisted of a semisynthetic low fluoride diet. The mice were kept in groups of ten in cages set at a temperture of 22-24 degC and of relative humidity 40-60%. The fluorescent light was 12 hours per day.
Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
Groups of 8-12 mice of each sex received 0, 10, 50, 100, 200, 300 or 600 ppm sodium fluoride in deionised water ad libitum for 6 months.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
The concentrations are nominal concentrations.
Duration of treatment / exposure:
26 weeks
Frequency of treatment:
Continuous (ad libitum, in drinking water)
Remarks:
Doses / Concentrations:
0, 10, 50, 100, 200, 300 or 600 ppm
Basis:
nominal in water
No. of animals per sex per dose:
The method stated ten mice of each sex per dose group. However, some of the test animals were incorrectly sexed, resullting in 8-12 mice per sex per dose group.
Control animals:
other: One control group received de-ionised water and a low fluoride diet. One control group received sodium chloride and a low fluoride diet. An additional control group received standard diet.
Details on study design:
Groups of 8-12 mice of each sex received 0, 10, 50, 100, 200, 300 or 600 ppm sodium fluoride (corresponding to approx. 0, 1.6, 8, 15.8, 31.5, 47.3, 59.5 mg fluoride/kg bw day) in deionised water ad libitum for 6 months. All test animals receiving water supplemented with sodium fluroide were provided with a low fluoride (<2.1 ppm) semisynthetic diet throughout the study. Three control groups were included in the studies of male and female mice; one received deionised drinking water and a low fluoride, semisynthetic diet, the second received sodium chloride supplemented deionized drinking water and a low fluoride, semisynthetic diet and the third received deionized water and a standard NIH-07 diet. At termination of the studies, the fluoride concentrations in urine, blood and bone were determined from samples collected from all surviving mice. Necropsy was performed on all animals, with histopathology at 300 and 600 ppm.
Positive control:
Not relevant
Observations and examinations performed and frequency:
Animals were observed twice daily for mortality and morbidity, weighed initially, once 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:
Necropsy was performed on all animals, with histopathological investigation of animals at 300 and 600 ppm.
Other examinations:
Fluoride concentrations in bone, blood and urine measured prior to necropsy
Statistics:
Not 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:
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
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
Deaths occurred at 600 ppm (4 males, 9 females) and at 300 ppm (1 male). Signs of toxiicity (weakness, thin appearance, hunched posture) were seen at 600 ppm. Mice at 100, 200, 300 and 600 ppm had chalky white teeth; the lower incisors were more affected and were also chipped at higher dose levels.

BODY WEIGHT AND WEIGHT GAIN
Reduced weight gain was seen at 200, 300 and 600 ppm; food consumption was reduced in males at 600 ppm. Water consumption was unaffected by treatment.

GROSS PATHOLOGY
None

HISTOPATHOLOGY
Treatment-related findings were noted in the kidney, liver, testes and myocardium of decedents. Acute nephrosis was characterised by extensive multifocal degeneration and tubular necrosis and was diagnosed as the cause of death in these animals. Multifocal myocardial degeneration was also seen in two 600 ppm females. Liver changes consisted of scattered heptocellular hypertrophy and megalocytosis. The effects on the testes (degeneration/necrosis of the seminiferous tunules) were not considered to be directly related to treatment, but occur frequently in moribund mice. Effects were also noted on teh femur and (to a lesser extent) the tibia of mice at 50 ppm and greater. Changes are considered to be indicative of altered rates of bone deposition and remodelling. Effects on the teeth were seen at 300 and 600 ppm.

OTHER FINDINGS
The fluoride content of plasma, bone and urine increased with dose level.
Dose descriptor:
NOAEL
Effect level:
10 ppm
Sex:
male/female
Basis for effect level:
other: Effects on bone
Dose descriptor:
LOEL
Effect level:
50 ppm
Sex:
male
Basis for effect level:
other: Effects on bone
Dose descriptor:
NOEL
Effect level:
50 ppm
Sex:
female
Basis for effect level:
other: Effects on bone
Critical effects observed:
not specified

Dose (ppm)

Survival

Mean Body Weight

Final Weight relative to control (%)

Initial

Final

Change

Male

Controla

9/9

16.9±0.4

40.2±1.0

23.3±1.1

100

Controlb

10/10

18.6±0.4*

41.6±0.6

23.0±0.7

103

Controlc

11/11

17.8±0.4

39.2±1.0

21.4±1.0

97

10

9/9

17.3±0.5

43.1±1.5

25.8±1.8

107

50

10/10

18.0±0.6

41.1±1.1

23.1±1.3

102

100

10/10

19.2±0.8

41.5±1.1

22.3±1.3

103

200

10/10

17.9±0.7

36.5±1.2

18.6±1.4*

91

300

7/8

18.8±0.7

38.1±1.1

19.0±1.4*

95

600

5/9

17.4±0.4

32.0±1.6**

14.8±1.9**

80

Female

Controla

11/11

16.9±0.6

30.2±1.4

13.3±1.6

100

Controlb

10/10

18.6±0.4

31.5±1.0

12.9±1.1

104

Controlc

9/9

16.6±0.2

28.7±0.9

12.1±0.8

95

10

11/11

17.1±0.4

29.6±1.1

12.5±1.1

98

50

10/10

16.4±0.3

32.2±1.1

15.8±1.2

107

100

10/10

17.2±0.4

30.6±1.5

13.4±1.4

101

200

10/10

17.2±0.4

25.3±0.6**

8.1±0.7*

84

300

12/12

16.9±0.3

26.2±0.8*

9.3±0.7*

87

600

2/11

16.6±0.4

24.5±1.5

9.0±1.0

81

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

**P<0.01

a         Control group receiving semisynthetic, low fluoride diet and deionised water.

b      Control group receiving semisynthetic, low fluoride diet and sodium chloride supplemented deionised water

c      Control group receiving standard NIH-07 diet and deionised water.

Organs and Diagnoses

300 ppm

600 ppm

Male

Animals initially in study

Early deaths

 

Kidney

Nephrosis, multifocal

 

Liver

Megalocytosis, multifocal

Syncytial alteration, multifocal

 

Myocardium

Mineralization, multifocal

 

Testis

Necrosis

Tubule, degeneration, multifocal

Tubule, multinucleated giant cells, multifocal

 

Female

 

Animals initially in study

Early deaths

 

Kidney

Nephrosis, multifocal

 

Liver

Megalocytosis, multifocal

Syncytial alteration, multifocal

 

Myocardium

Degeneration, multifocal

Mineralization, multifocal

 

8

1

 

 

1

 

 

1

1

 

 

1

 

 

1

 

1

 

 

 

12

0

 

 

0

 

 

0

0

 

 

0

0

 

9

4

 

 

2

 

 

4

4

 

 

4

 

 

3

2

1

 

 

 

11

9

 

 

2

 

 

7

7

 

 

2

4

Conclusions:
In this study a NOAEL of 10 ppm corresponding to fluoride doses of 1.6 mg/kg bw/day was obtained for systemic toxicity in mice.
Executive summary:

Groups of 8 to 12 B6C3F1 mice of each sex were administered 0, 10, 50, 100, 200, 300 or 600 ppm sodium fluoride (corresponding to approx. 0, 1.6, 8, 15.8, 31.5, 47.3, 59.5 mg fluoride/kg bw day) in deionized water ad libitum for 26 weeks. Mortality was observed in 4/9 males and 9/11 females receiving 600 ppm sodium fluoride and 1/8 male given water containing 300 ppm. The fluoride content of urine and bone increased with the concentration of sodium fluoride in the drinking water in both sexes of mice. Bone fluoride concentration were as high as 14.8 µg/mg of ashed bone in male mice receiving 600 ppm sodium fluoride in water. Plasma fluoride concentrations in mice showed a good dose relationship and appeared increased in groups receiving water concentrations of 50 ppm of sodium fluoride or higher. The acute nephrosis observed in the kidneys was probably the most likely cause of death. Compound-related effects were observed in the femur and, to a lesser extent, in the tibia of nearly all male and female mice receiving 100 to 600 ppm sodiumfluoride and 5/10 males receiving 50 ppm. Therefore the LOAEL was determined to be 50 ppm (8 mg fluoride/kg bw/day). A NOAEL of 10 ppm corresponding to fluoride doses of 1.6 mg/kg bw/day was obtained for systemic toxicity in mice.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: High quality range-finding study for the NTP carcinogenicity study.
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
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.
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:
26 weeks.
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 (corresponding to approx. 0, 0.28, 0.84, 2.8, 8.4 mg fluoride//kg bw/day), 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
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.
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:
From the results of the present study in rats, it was concluded that the most critical effects of the substance after repeated oral exposure were effects on the teeth (dental fluorosis) and stomach. The overall NOAEL for systemic effects is 100 ppm sodium fluoride (approx. 2.8 mg fluoride/kg bw/day)
Executive summary:

Groups of 10 F334/N rats of each sex were administered 0, 10, 30, 100 or 300 ppm sodium fluoride in deionized water (corresponding to approx. 0, 0.28, 0.84, 2.8, 8.4 mg fluoride//kg bw/day) ad libitum for 26 weeks.

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. The fluoride content of plasma, bone and teeth increased with dose levels (NTP 1990).

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. Therefore 100 ppm of NaF in the drinking water (approx. 2.8 mg fluoride/kg bw/day) was considered a NOAEL in this 6-month rat study.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
7.4 mg/kg bw/day
Study duration:
chronic
Species:
mouse
System:
other:
Organ:
bone
tooth

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No data on the repeated dose toxicity are available for barium fluoride and therefore this endpoint was assessed in a "Weight-of-Evidence" approach in accordance with section 1.2 of REACH Annex XI. Under physiological conditions barium fluoride will dissociate into barium and fluoride ions. Therefore the toxicity of barium fluoride may reasonably be considered to be determined by the availability of Ba2+ cations and F- anions. Comprehensive data on repeated dose toxicity are available for barium chloride and sodium fluoride. As a first surrogate for bioavailability, the water solubility of a test substance may be used. Both barium chloride and sodium fluoride are highly water soluble with ca. 375 g/L and 40 g/L, respectively at neutral pH, whereas barium fluoride has a solubility of 1.6 g/L. Hence, any read across from barium chloride and sodium fluoride to BaF2 is inherently conservative.

Fluoride - Repeated dose oral toxicity

Comprehensive repeated dose toxicity studies by oral route are available for sodium fluoride. In a 6-month oral (drinking water) rat study, groups of 10 F334/N rats of each sex were administered 0, 10, 30, 100 or 300 ppm sodium fluoride (corresponding to approx. 0, 0.28, 0.84, 2.8, 8.4 mg fluoride/kg bw/day) in deionized water ad libitum for 26 weeks (NTP, 1990). 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. The fluoride content of plasma, bone and teeth increased with dose levels. 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. Therefore 100 ppm of NaF in the drinking water (approx. 2.8 mg fluoride/kg bw/day) was considered a NOAEL in this 6-month rat study. This value corresponds to approx. 13 mg barium fluoride/kg bw/day.

In a 6-month oral mouse study, groups of 8 to 12 B6C3F1 mice of each sex were administered 0, 10, 50, 100, 200, 300 or 600 ppm sodium fluoride (corresponding to approx. 0, 1.6, 8, 15.8, 31.5, 47.3, 59.5 mg fluoride/kg bw/day) in deionized water ad libitum for 26 weeks. Mortality was observed in 4/9 males and 9/11 females receiving 600 ppm sodium fluoride and 1/8 male given water containing 300 ppm. The fluoride content of urine and bone increased with the concentration of sodium fluoride in the drinking water in both sexes of mice. Plasma fluoride concentrations in mice showed a good dose relationship and appeared increased in groups receiving water concentrations of 50 ppm of sodium fluoride or higher. The acute nephrosis observed in the kidneys was probably the most likely cause of death. Compound-related effects were observed in the femur and, to a lesser extent, in the tibia of nearly all male and female mice receiving 100 to 600 ppm sodium fluoride and 5/10 males receiving 50 ppm. Therefore the LOAEL was determined to be 50 ppm (8 mg fluoride/kg bw/day). A NOAEL of 10 ppm corresponding to fluoride doses of 1.6 mg/kg bw/day was obtained for systemic toxicity in mice. This value refers to approx. 7.4 mg barium fluoride/kg bw/day.

Barium - Repeated dose toxicity: oral

The reference Dietz (1992) is considered as the key study for repeated dose toxicity of barium via oral application. In this study, barium chloride dihydrate was administered for 92 days to Fischer 344/N rats in drinking water at levels of 0, 125, 500, 1000, 2000, and 4000 ppm. Mortality was observed in 3/10 males and 1/10 females in the 4000 ppm group. Depressed body weight gains, elevated phosphorus levels and chemically related lesions in the kidney and lymphoid tissue were observed at the highest dose level of 4000 pm. At 4000 ppm, motor activity, grip strength, and thermal sensitivity were marginally affected. These effects were probably secondary changes resulting from barium chloride toxicity observed at this dose level. Individual effects observed at 2000 ppm barium chloride in drinking water (corresponding to the final barium dose of 61.1 and 80.9 mg Ba/kg bw/day to male and female rats respectively) were regarded as not treatment-related and this dose level represents the NOAEL. These results correspond to a NOAEL of approx. 78 - 103 mg Barium fluoride/kg bw/day.

Repeated dose toxicity: dermal

Additional testing by dermal route is not applicable as data on repeated dose oral / systemic toxicity was provided. According to the REACH Regulation (EC) No 1907/2006, Annex VIII, 8.6.1, only one repeated dose toxicity study is required (with administration via the most appropriate route).

Repeated dose toxicity: inhalation

Additional testing by inhalation route is not required as data on repeated oral / systemic toxicity is provided. According to REACH regulation 1907/2006, Annex VIII, 8.6.1 only one repeated dose toxicity study with administration via the most appropriate route is required

Conclusion

Barium fluoride will dissociate under physiological conditions to form barium and fluoride ions. Since no data on the repeated dose toxicity are available for barium fluoride, the available studies with sodium fluoride and barium chloride were used to assess the toxicity of Ba2+ and F- ions. The calculated oral NOAEL of barium fluoride based on the NOAEL of fluoride (7.4 mg/kg bw/day) is lower than the calculated NOAEL of barium fluoride based on the NOAEL of barium (78 mg/kg bw/day) therefore it is concluded that the critical systemic toxic effects of barium fluoride will be due to fluoride.

Justification for classification or non-classification

The classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – repeated exposure, oral are not met because the effects observed in the available repeated dose toxicity studies can not be regarded as "significant" or "severe", and do not indicate functional disturbance or morphological changes of toxicological relevance. For this reason, no classification for specific target organ toxicant (STOT) – repeated exposure, oral is required.

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