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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: relevant supporting study to demonstrate data for Cl2 release for sodium hypochlorite

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1979

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
not specified
Principles of method if other than guideline:
No guideline indicated as study is a 6 weeks inhalation study. The conduct was similar to OECD guideline 412 "Repeated Dose Inhalation Toxicity: 28 day or 14 day Study".
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Chlorine
EC Number:
231-959-5
EC Name:
Chlorine
Cas Number:
7782-50-5
Molecular formula:
Cl2
IUPAC Name:
chlorine
Details on test material:
Chlorine gas
Chlorine and nitrogen mixture

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
other: no data
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
30 days (6 weeks)
Frequency of treatment:
5 days/week, 6 h per day
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 1.0, 3.0 and 9.0 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
1.0±0.04 ppm, 3.0±0.1 ppm, 8.99±0.45
Basis:
analytical conc.
Control animals:
other: air control group
Details on study design:
Post-exposure period: none

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 specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
The results of this study indicated that unequivocal upper and lower respiratory tract change were produced in Fischer 344 rats exposed to 9 ppm of chlorine. This conclusion was supported by the clinical signs of generalised respiratory tract irritation, increased lung weights and lung to body weight ratios, and the histopathological changes which extended throughout the upper and lower respiratory tract of rats exposed to 9 ppm. The increases in the total number of segmented neutrophils at 9 ppm correlated very well with the inflammation and mucopurulent exudate of the upper and lower respiratory tract. The respiratory tract effects found in animals exposed to 3 or 1 ppm chlorine were very similar and much less severe than those seen at 9 ppm. Concentration-dependent elevations were seen in urine specific gravity at all exposure concentrations in females and 9 or 3 ppm in males. Blood urea nitrogen was raised in both sexes exposed to 9 ppm . The kidneys of both sexes were darkened in appearance and the histopathological examination of males exposed to 9 ppm showed swelling of the epithelial cells of the proximal convoluted tubules with increased eosinophilic cytoplasmic homogeneity and decreased granularity. The presence of renal effects was also supported by clinical observation of urinary staining and matting of the fur around the genitalia in both sexes exposed to 9 or 3 ppm chlorine. Evidence of hepatic effects were seen from elevations of the activity of several enzymes. A concentration-related increase in alkaline phosphates was seen in rats of both sexes exposed to 9 or 3 ppm. Additionally, gamma-glutamyl transpeptidase was elevated in both sexes exposed to 9 ppm and serum glutamic pyruvic transaminase was elevated in females at 9 ppm. Animals exposed to 9 ppm showed an increased hepatocellular cytoplasmic eosinophilic homogeneity. Furthermore, an increase in the degree of hepatocellular cytoplasmic vaculation was seen at 9 or 3 ppm. The spleen and thymus of rats exposed to 9 ppm showed a decreased content of lymphoid elements. This finding correlated with the statistically significant decreases in absolute and relative weights of these two organs at 9 ppm which may have been a function of the poor physical condition and decreased nutritional fate of these rats. Ulceration and oedema of the stomach wall was found in both sexes exposed to 9 ppm. A plausible explanation for this observation includes general stress or ingestion of hydrochloric and/or hypochlorous acids as a result of natural grooming or deposition in the oral cavity, either directly or via the mucus escalator.

Effect levels

Dose descriptor:
LOAEL
Effect level:
<= 3 mg/m³ air
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The described observations indicated that repeated exposure of Fischer 344 rats to chlorine resulted in pulmonary effects at all level used, and hepatic and renal effects at 9 and 3 ppm chlorine. However, these results are difficult to interpret as they pertain to human exposures largely because of differences between rats and humans regarding pulmonary anatomy, patterns of respiration, and amount of pulmonary ventilation. A LO(A)EL of 1.0 ppm corresponding to 3.0 mg/m3 (0.806 mg/kg bw/d assuming a body weight of 320 g and a respiratory volume of 0.086 m3/6 h) but no NO(A)EL was found.
Executive summary:

The results of this study indicated that unequivocal upper and lower respiratory tract change were produced in Fischer 344 rats exposed to 9 ppm of chlorine. This conclusion was supported by the clinical signs of generalised respiratory tract irritation, increased lung weights and lung to body weight ratios, and the histopathological changes which extended throughout the upper and lower respiratory tract of rats exposed to 9 ppm. The increases in the total number of segmented neutrophils at 9 ppm correlated very well with the inflammation and mucopurulent exudate of the upper and lower respiratory tract. The respiratory tract effects found in animals exposed to 3 or 1 ppm chlorine were very similar and much less severe than those seen at 9 ppm. Concentration-dependent elevations were seen in urine specific gravity at all exposure concentrations in females and 9 or 3 ppm in males. Blood urea nitrogen was raised in both sexes exposed to 9 ppm . The kidneys of both sexes were darkened in appearance and the histopathological examination of males exposed to 9 ppm showed swelling of the epithelial cells of the proximal convoluted tubules with increased eosinophilic cytoplasmic homogeneity and decreased granularity. The presence of renal effects was also supported by clinical observation of urinary staining and matting of the fur around the genitalia in both sexes exposed to 9 or 3 ppm chlorine. Evidence of hepatic effects were seen from elevations of the activity of several enzymes. A concentration-related increase in alkaline phosphates was seen in rats of both sexes exposed to 9 or 3 ppm. Additionally, gamma-glutamyl transpeptidase was elevated in both sexes exposed to 9 ppm and serum glutamic pyruvic transaminase was elevated in females at 9 ppm. Animals exposed to 9 ppm showed an increased hepatocellular cytoplasmic eosinophilic homogeneity. Furthermore, an increase in the degree of hepatocellular cytoplasmic vaculation was seen at 9 or 3 ppm. The spleen and thymus of rats exposed to 9 ppm showed a decreased content of lymphoid elements. This finding correlated with the statistically significant decreases in absolute and relative weights of these two organs at 9 ppm which may have been a function of the poor physical condition and decreased nutritional fate of these rats. Ulceration and oedema of the stomach wall was found in both sexes exposed to 9 ppm. A plausible explanation for this observation includes general stress or ingestion of hydrochloric and/or hypochlorous acids as a result of natural grooming or deposition in the oral cavity, either directly or via the mucus escalator.