Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
November 1957 - July 1958
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well documented study report (no GLP) which meets basic scientific principles.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1960

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups of albino rats and dogs were exposed to aerosols of boron oxide in dynamic chambers. The rats were individually caged in racks, 10 cages each, which were randomly changed for each exposure. The animals were exposed for 6 hours a day for 5 days a week.
70 rats exposed for 24 weeks 77 mg/m³,
4 rats exposued for 12 weeks, 175 mg/m³
20 rats exposed for 10 weeks, 470 mg/m³
3 dogs exposed for 23 weeks , 57 mg/m3.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
other: rats and dogs (only females)
Strain:
other: rats (albino)
Sex:
male/female
Details on test animals and environmental conditions:
No further data available

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
not specified
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: Rats:
Dose group of 77 mg/m³: 2.5 microns;
Dose group of 175 mg/m³: 1.9 microns;
Dose group of 470 mg/m³: 2.4 microns;
Dogs:
Dose group of 57 mg/m³: 2.4 microns.
Details on inhalation exposure:
Groups of albino rats and dogs were exposed to aerosols of boron oxide in four dynamic chambers having volumes of 20, 100, 1000, and 1000 liters, respectively. The rats were individually caged in racks, 10 cages each, which were randomly changed for each exposure. The animals were
exposed for 6 hours a day for 5 days a week.
Boron oxide, which was presized, was dispersed from modified Wright dust dispersers into the chambers at a fairly constant rate throughout the exposure period. Large particles were eliminated by means of a settling column between the disperser and the mixing bowl, where air entered the top of the chamber. A flow of room air of about half of the chamber volume per minute was maintained.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples for determination of airborne concentrations of boron oxide were withdrawn from the chambers every hour and collected by means
of a filter paper sampler containing 5/ 8-inch disc s of Knowlton filter paper, Grade 100. The boron oxide was dissolved in water and the amount estimated by the carmine sulfuric-acid method. Standard solutions of boron oxide were run with every set to reduce possible errors in time of color development, acid concentration, or temperature. Samples for particle-size determinations of the aerosol were collected by means of a modified Cascade impactor, and mass median diameters (MMD) were derived by use of predetermined stage calibrations for boron oxide.
Duration of treatment / exposure:
Rats:
Dose group of 77 mg/m³: 24 weeks;
Dose group of 175 mg/m³: 12 weeks;
Dose group of 470 mg/m³: 10 weeks;
Dogs:
Dose group of 57 mg/m³: 23 weeks
Frequency of treatment:
6 hours a day for 5 days a week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
77, 175 and 470 mg/m³ (rats)
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
57 mg/m³
Basis:
nominal conc.
No. of animals per sex per dose:
Rats:
Dose group of 77 mg/m³: 70 animals;
Dose group of 175 mg/m³: 4 animals;
Dose group of 470 mg/m³: 20 animals;
Dogs:
Dose group of 57 mg/m³: 3 animals.
Control animals:
yes
Details on study design:
No data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

HAEMATOLOGY: Yes (see table 6 in "Results)

CLINICAL CHEMISTRY: Yes (see table 2 and 3 in "Results")

URINALYSIS: Yes
- Metabolism cages used for collection of urine: Yes
The urine of control and exposed rats was analyzed for boron by spectrographic methods.

OTHER:
- The fragilition of rat femurs, as measured by the breaking point, is shown in table 5. The ratio of the fracture weight in kg to the least diameter in mm was taken as the index for comparison of bone fragilition.
- Roentgenograms of control rats and those exposed to 77 mg/m³ were made.
Sacrifice and pathology:
- Tissues of the lungs, trachea, pancreas, thyroids, adrenals, eyes, femurs, ribs, bone marrow, liver, heart, spleen, kidneys, brain, stomach, intestines, ovaries, testes, lymph nodes, and muscles have been examined histologically for evidence of pathology.
Samples of the above tissues of exposed and control animals were dissolved in 20% sodium hydroxide and analyzed spectrographically for boron content.

- The percentage of body weight of heart, lungs, liver, and kidneys from five rats exposed to the aerosol for 20 weeks was compared with control rats.
Other examinations:
No data
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
a slight reddish exudate from the nose (470 mg/m³)
Mortality:
mortality observed, treatment-related
Description (incidence):
a slight reddish exudate from the nose (470 mg/m³)
Body weight and weight changes:
no effects observed
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:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
considerable differences in the pH, volume, and creatinine coefficient.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
onsiderable amounts of boron were excreted by the exposed rats and averaged 11.90 mg/kg/day
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
At no time were any toxic signs noticed, nor were there any deaths from inhalation of the boron-oxide aerosol. However, some of the rats exposed to a concentration of 470 mg/m³ had a slight reddish exudate from the nose. Since these animals were covered with the dust there was probably local irritation of the external nares and some irritation from scratching. This concentration produced a dense cloud of fine particles. Workers experienced in the aerosol field expressed their belief that visibility in such a cloud would probably be limited to 10 to 12 feet.

BODY WEIGHT AND WEIGHT GAIN
The weight changes of control and exposed aniamls are shown in figure 2 (please see attached). Since female rats bad almost reached full growth at the time of initiation of therre exposures, whereas males far from their peak growth were used, the different growth rates of the two sexes are not believed to be attributable to the exposure.The control rats grew about 9% faster than those exposed to a concentration of 470 mg/m³, whereas those exposed to 77 mg/m³ gained the same amount or slightly more than their controls for the same period of time. The mature dogs showed slight fluctuations in weight but no general trend in either direction.

HAEMATOLOGY
There was a slight and probably insignificant rise in the leucocyte counts of the exposed dogs that may suggest a slight response to poisoning
by the aerosol. There were no other changes, except for the usual fluctuations, and no significant difference from the control (table 6).


CLINICAL CHEMISTRY
There were no modifications in the sugar or albumin content of the urine of the exposed rate and the controls. There were considerable
differences, however, in the pH, volume, and creatinine coefficient, as shown in table 2. The changes were analyzed by the T-test and found to be significantly different, with the following values of probability: volume P = 5%, pH and creatinine coefficient P = 1%. The formation of boric acid by hydration in the body probably caused the greater acidity of the urine of the exposed rats. The increased volume is undoubtedly accounted for by the known diuretic property of boric acid. The cause of increased creatinine excretion is not known. These values returned to normal a week after termination of the exposure.
Chemical analyses of six common blood constituents are given in table 3, for groups of rats exposed for 24 weeks to two concentrations of aerosols. There were no constant changes in either direction and no significant difference from the control values. Since no control values were determined
for the female rats the possible significance of apparent changes in sugar and lactic acid were undetermined.

In table 7 are given the results of the chemical analyses of some constituents of the dog blood. As with the rat blood, there were no changes from the pre-exposure values nor from those of the control dog. Sulfobromophthalein retention tests, for liver damage, were also negative as compared to the control.

URINALYSIS
The urine of control and exposed rats was analyzed for boron by spectrographic methods. The data show that considerable amounts of boron were excreted by the exposed rats and averaged 11.90 mg/kg/day. The controls excreted 0.24 mg/kg/day, or about 10 µg/mL. The data are presented
in table 4.

ORGAN WEIGHTS
The percentage of body weight of heart, lungs, liver, and kidneys from five rats exposed to the aerosol for 20 weeks was compared with control
rats. The differences were not significant.

HISTOPATHOLOGY: NON-NEOPLASTIC
No differences were noted between the tissues of the exposed and control animals. There were no signs of pneumoconiosis. Samples of the tissues of exposed and control animals were dissolved in 20% sodium hydroxide and analyzed spectrographically for boron
content. Standard solutions of boron oxide in water were aaalyzed and showed that by the method a minimum of 2.5 µg/mL of boron could be detected. The use of the method would have detected 0.011% of boron in the lung sample analyzed and a thid that amount in the other tissues. The rats had been exposed for 6 weeks to a concentration of 77 mg/m³ of boron oxide. There was no boron found in any of the samples. The rats were, however, in metabolism cages for 60 hours after exposure and before being killed. If boron had been present, it is possible that it was eliminated during that time.

OTHER FINDINGS
The fragilition of rat femurs, as measured by the breaking point, is shown in table 5. The ratio of the fracture weight in kg to the least diameter in mm was taken as the index for comparison of bone fragilition. There was no significant difference between the controls and those exposed to the aerosol, as shown by the t- test.
Roentgenograms of control rats and those exposed to 77 mg/m³ of boron oxide for 10 weeks showed no detectable effects.

Effect levels

open allclose all
Dose descriptor:
NOAEC
Remarks:
systemic (rats)
Effect level:
470 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No systemic effects were noted at this dose level
Dose descriptor:
NOAEC
Remarks:
local (rats)
Effect level:
175 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: due to local effects (slight reddish exudate from the nose) observed in animals at 470 mg/m³
Dose descriptor:
NOAEC
Remarks:
systemic (dogs)
Effect level:
57 mg/m³ air (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No changes or toxic signs were noted.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1. Exposure animals to aerosols of boron oxide

Species

No.

Chamber size

Average concentration

Duration of exposure

Particle size, MMD

liters

mg/m³

weeks

microns

Rat

70

1000

77

24

2. 5

Rat

4

20

175

12

1.9

Rat

20

100

470

10

2.4

Dog

3

1000

57

23

2. 4

Table 2. The pH, volume and creatinine coefficient for urine of control and of exposed rats (concentration 77 mg/m³)

Weeks of exposure

pH

Volume

Creatinine coefficient

Exposed

Control

Exposed

Control

Exposed

Control

ml/kg/day

mg/kg/day

4

8.66

8.94

30

12

14.7

2.2

6

-

33

43

9.3

4.0

8

8.30

8.85

44

20

13. 9

1.6

10

-

-

52

24

18. 1

3. 6

12

-

-

41

21

17. 2

3.8

14

-

-

55

22

12. 1

10.8

16

8.24

8.94

28

13

18. 1

7.6

18

8.16

8.78

23

11

16.3

11.8

20

7.38

9.05

17

11

17. 9

11.2

22

8.24

8.90

24

17

14. 9

7.2

Average

8.16

8.91

34.7

19.4

15.3

6.4

Table 3. Chemical analyses of the blood of rats exposed to aerosols of boron oxide

Time of exposure

Sugar

Lactic acid

Protein

Inorganic phosphorus

Creatinine

Cholesterol

weeks

mg

%

g %

m %

Females exposed to 470 mg/m³

2

119

29

5.9

10. 5

1.0

-

4

53

50

5. 5

8.4

1.2

-

6

52

52

7. 5

-

-

-

8

* 78

30

6. 6

4. 7

-

-

10

55

60

7.4

5.1

-

-

Males exposed to 77 mg/m³

2

116

37

7.2

5.6

-

-

4

120

14

9.6

4.4

-

-

6

87

47

5.8

4.2

0.8

-

8

80

39

6.5

5.0

1.2

-

10

120

32

6.2

4.4

0.9

-

12

59

28

4.5

5.4

0.8

-

14

88

29

7. 3

5.1

0.9

-

16

104

30

6. 7

5.2

1.0

83

18

86

27

6.8

4.4

0. 6

-

20

161

13

7.4

4.6

1.0

91

22

138

37

6.8

5. 1

0.8

121

24

82

55

7.5

4. 7

0.5

127

Average

103

32

6.8

4.8

0.94

101

Male controls (13 samples)

Average

104

37

6.8

5.5

1.04

100

Table 4. Boron content of urine control rats and of rats exposed to aerosols of boron oxide

Weeks of exposure

Urinary boron content*

(mg/kg/day)

 

Controls

Exposed

2

-

16.6

4

0.7

12.3

6

0.2

7.4

8

0.3

1.9

10

0.2

5.5

12

0.1

23.2

14

0.2

2.8

16

0.1

20.7

18

0.1

20.7

20

0.3

7.0

22

0.2

12.7

Average

0.24

11.9

* When the urine of the rats was analyzed a week after the end of the period of exposure, the boron content in the urine of the control rats and exposed rats was 0.3 mg/kg/day. After a 2-week interval, the boron content in the urine of the control rats wae 0.5 mgjkglday; in the urine of the exposed rats, it was 0.9 mg/kg/day.

Table 5. Fragility of femurs of control rats and rats exposed to an aerosol of boron dioxide

Group

No.

Least diameter

Fracture weight

Fracture weight

least diameter

Standard deviation

mm

kg

av*

Controls

14

2.68

6.6

2.43

0.69

Exposed*

8

2.70

6.2

2.30

0.87

* Arerages of groups that had been exposed for 6 and 10 weeks to a concentraam of 470 mg/m³

Applicant's summary and conclusion

Conclusions:
No toxic signs were evident in any of the animals. NOAEC of 470 mg/m³ for systemic toxicity in rats is established based on the study results. NOAEC of 175 mg/m³ is appropriate for local effects due to irritation of noses of rats. NOAEC of 57 mg/m³ for dogs is based on the absence of any toxic effect.
Executive summary:

Groups of albino rats and dogs were exposed to aerosols of boron oxide in dynamic chambers. The rats were individually caged in racks, 10 cages each, which were randomly changed for each exposure. The animals were exposed for 6 hours a day for 5 days a week. 70 rats were exposed for 24 weeks (77 mg/m³), 4 rats were exposued for 12 weeks (175 mg/m³), 20 rats were exposed for 10 weeks (470 mg/m³) and 3 dogs were exposed for 23 weeks to 57 mg/m³. The test concentrations were verified analytically and mass median diameters (MMAD) were derived.

No toxic signs were evident in any of the animals. All groups of rats exposed to concentrations of 77 and 470 mg/m³ gained weight at about the same rate as their controls.Chemical analyses of dog and rat blood, and urine showed no changes from control values, except for an increased urinary excretion of creatinine in the rats, and lower pH, increased volume, and increased boron content in the rat urine. No changes were found as a result of aerosol exposures in the following:

1. rattissues and organs

2. bone fragility

3. roentgenograms of rat bones

4. hematology of dog blood

5. sulfobromophthalein retention

6. rat organ weight.