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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Original reference in a foreign language

Data source

Reference
Reference Type:
publication
Title:
[Experimental data for hygienic standardization of bromine and hydrogen bromide content in the air of working areas]
Author:
Ivanov NG, AM Klyachkina, AL Germanova
Year:
1976
Bibliographic source:
Gig. Tr. Prof. Zabol. 20:36-39.

Materials and methods

GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Bromine
EC Number:
231-778-1
EC Name:
Bromine
Cas Number:
7726-95-6
Molecular formula:
Br2
IUPAC Name:
dibromine

Test animals

Species:
rat
Strain:
other:
Sex:
male/female

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
4 month exposure, with 1 month recovery group
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
12.4 mg/m3
Basis:
other: ± 1.4 mg/m3
Remarks:
Doses / Concentrations:
1.4 mg/m3
Basis:
other: ± 0.1 mg/m3
Remarks:
Doses / Concentrations:
0.16 mg/m3
Basis:
other: ± 0.632 mg/m3
No. of animals per sex per dose:
8 rats or 6 rabbits were the minimum statistical groups
Control animals:
yes
Details on study design:
- Dose selection rationale: The LIMir from the acute study, 9 times lower than the LIMir and 80 times lower than LIMir
The LIMir was the air concentration seen as the limiting dose for irritation, approximately 10 mg/m^3 for a 4 hour exposure. In the chronic exposure experiment, actual concentrations were 12.4 +/- 1.4 mg/m^3, 1.4 +/-0.1 mg/m^3, and 0.16 +/- 0.632 mg/m^3.
- Post-exposure recovery period in satellite groups: 1 month

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Primarily respiratory tract irritation
Mortality:
mortality observed, treatment-related
Description (incidence):
Primarily respiratory tract irritation
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Decreased body weights
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
thyroid and adrenal gland
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Respiratory system
Details on results:
Exposure to 12.4 +/- 1.4 mg/m^3 (1.9 ppm) for 4 months caused effects on the respiratory, olfactory, and endocrine systems. Less pronounced effects were seen with exposure to 1.4 +/- 0.1 mg/m^3 (0.2 ppm) for four months, which were seen to be reversible in a 1 month recovery group. No effects were seen as a result of exposure to 0.16 mg/m^3 (0.02 ppm) for 4 months. See table in Other information on results
The high exposure concentration caused pronounced toxic effects. Rats showed decreased body weights, and effects on the functions of the nervous, endocrine and cardiovascular systems. Disruption of the respiratory system was seen at all periods of observation throughout the exposure. Respiratory rates in the rats exposed to the high concentration were reduced compared to control, and also at 2 months of exposure. Hitopathology in the high dose exposed animals was primarily respiratory lesions, with signs of moderate protein dystrophy were seen in kidney and liver. In a parallel experiment using rabbits, respiratory rate effects were also seen at 2 and 3 months after start of exposure, and the olfactory thresholds to exposure to aromatic substances were increased in rabbits. At 1 month after start of exposures in rabbits, the olfactory threshold to tar increased four fold, and after 4 months, increased 10 fold. These changes in rabbits persisted even in the 1 month recovery period. Histopathology of rabbits showed that the respiratory system was the main lesion, with moderate protein dystrophy in the liver and kidneys also.
With exposure to the middle concentration (1.4 mg/m^3 +/- 0.1), decreased excitability of the nervous system was measured at 3 months. Changes in the endocrine system were somewhat biphasic. At 2 months of exposure, thyroid uptake of 131Iodine was increased in the treated animals compared to controls, and weight coefficients of the thyroid glands were increased. At 4 months, the thyroid functions appeared decreased as indicated by decreased lablled iodine uptake. Adrenal weights were increased at 3 months of exposure. The respiratory effects in the mid-concentration group were more constant - respiratory rates were decreased in the rats at 2 months. Rats showed progressive decrease in olfactory acuity during the exposure period. Decrease in olfactory acuity was closely associated with the changes in the mucous membranes of the upper respiratory tract. The histopathology seen in the respiratory system of the high and mid concentration exposure groups included thickening of the mucous membrane and submucosal layers, edema, increased number of goblet cells in the epithelium, desquamation of epithelial cells, and discharge of mucus into the clear spaces of the upper respiratory tracts. Effects were more pronouced in animals exposed to the concentration representing LIMir (the highest concentration). Effects were less in the mid-dose concentration, and all the tested characteristics in this dose group normalized in the 1 month recovery period. this suggested that the middle concentration was close to the LIMch (limit for chronic effects). The lowest concentration (0.16 mg/m^3) was seen to cause no adverse effects in the selected endpoints.

Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
0.16 mg/m³ air
Basis for effect level:
other: overall effects: no effects seen. This concentration was considered 80 times lower than the limit of irritation (LIM ir).
Dose descriptor:
LOAEC
Effect level:
1.4 mg/m³ air
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

4 month repeated dose study in rats

Effect Observed

Control Group

Concentration Group

Significance Level or Comment

Respiratory rate (per minute)

Month 1

Month 2

Control

163 +/- 3.6

170 +/- 5.9

12.4 mg/m^3

124 +/- 2.6

138 +/- 4.5

P < 0.001

P < 0.001

Respiratory rate (per minute)

Month 2

Control

170.0 +/- 5.9

1.4 mg/m^3

146.0 +/- 3.3

P > 0.002

Olfactory Acuity

Control

1.4 mg/m^3

Decreased

Disruptions of Cardiovascular, Nervous and Endocrine Systems

Control

12.4 mg/m^3

1.4 mg/m^3

Present

Decreased Nervous Excitability

Measured in units

Month 3

Control

3.8 +/- 0.13

1.4 mg/m^3

5.1 +/- 0.2

P < 0.001

Endocrine Effects:

131I absorption by thyroid:

Month 2

Month 4

Control

14.5 +/- 1.3%

24.3 +/- 2.9%

1.4 mg/m^3

38.4 +/- 5.3%

9.1 +/- 0.74%

P < 0.001

P < 0.001

Effect on organ weight coefficients:

Thyroid: Month 2

Adrenal: Month 3

Control

5.7 +/- 0.21

17 +/- 0.79

1.4 mg/m^3

6.8 +/- 0.31

21 +/- 1.19

P = 0.01

P = 0.02

Histopathology of nose mucous membranes

Histopathology of liver, kidneys

12.4 mg/m^3

1.4 mg/m^3

Effects seen

12.4 mg/m^3

Increased thickness of mucous membrane and submucosal layer, edema, increased epithelial goblet cells, desquamation of epithelial cells, increased mucous in open passages

moderate protein dystrophy in kidneys, liver

No adverse effects seen

Control

0.16 mg/m^3

Applicant's summary and conclusion

Conclusions:
A 4 month bromine inhalation exposure study in rats produced a No adverse effects concentration of 0.16 mg/m^3 (0.02 ppm). The lowest concentration producing effects was 1.4 mg/m^3 (0.2 ppm) for a 4 month exposure. Effects were seen in the respiratory, olfactory and endocrine systems, although these effects were less pronounced than those seen with exposure to 12.4 mg/m^3 (1.9 ppm), and the effects were reversible as demonstrated in a 1 month recovery group. The LIMir concentration (12.4 mg/m^3) produced signs of pronounced toxicity. A parallel study in rabbits showed similar effects - with the respiratory system as the main target organ.
Executive summary:

A 4 month bromine inhalation exposure study in rats produced a no adverse effects concentration of 0.16 mg/m^3 (0.02 ppm). The lowest concentration producing effects was 1.4 mg/m^3 (0.2 ppm) for a 4 month exposure. Effects were seen in the respiratory, olfactory and endocrine systems, although these effects were less pronounced than those seen with exposure to 12.4 mg/m^3 (1.9 ppm), and the effects were reversible as demonstrated in a 1 month recovery group. The LIMir concentration (12.4 mg/m^3) produced signs of pronounced toxicity. A parallel study in rabbits showed similar effects - with the respiratory system as the main target organ.