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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
repeated dose toxicity: inhalation, other
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Justification for type of information:
The study described in this section is a key study in the RAC (2012) opinion on benzoic acid with the reference Rop, D. A., IRDC Report no: 163-676 (1981)

Data source

Reference
Reference Type:
other: Background document for RAC oppinion on benzoic acid
Title:
Background document to the Opinion proposing harmonised classification and labelling at EU level of Benzoic acid, CHL report
Author:
Committee for Risk Assessment, RAC
Year:
2012
Bibliographic source:
Background document to the Opinion proposing harmonised classification and labelling at EU level of Benzoic acid, CHL report, Committee for Risk Assessment, RAC, November 2012, ECHA/RAC/CLH-O-0000001687-65-02/A1
Report date:
2012

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
no
Remarks:
Study was performed before 1. of June 2008

Test material

Constituent 1
Chemical structure
Reference substance name:
Benzoic acid
EC Number:
200-618-2
EC Name:
Benzoic acid
Cas Number:
65-85-0
Molecular formula:
C7H6O2
IUPAC Name:
benzoic acid
Test material form:
not specified

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
not specified
Vehicle:
other: no vehicle, exposure to particles of the substance
Mass median aerodynamic diameter (MMAD):
4.7 µm
Details on inhalation exposure:
5 d/wk, 6 h/d for 4 weeks
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/L air
Remarks:
Controls
Dose / conc.:
0.025 mg/L air
Dose / conc.:
0.25 mg/L air
Dose / conc.:
1.2 mg/L air
No. of animals per sex per dose:
10

Examinations

Observations and examinations performed and frequency:
Evaluation of survival, body weight and organ weight and microscopic examinations

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Evaluation of survival, body weight and organ weight demonstrated significant systemic toxicity including 2/20 mortalities at the top dose of 1.2 mg/L. A reddish discharge around the nares was observed at doses ≥ 0.25 mg/L.
Mortality:
mortality observed, treatment-related
Description (incidence):
2/20 mortalities at the top dose of 1.2 mg/L.
Body weight and weight changes:
effects observed, treatment-related
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Decrease in platelet count
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
decrease in liver and kidney weight
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Interstitial inflammation, lung fibrosis at all doses
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Compound-related microscopic lesions consisting of multifocal to generalised inflammatory cell infiltrates and interstitial fibrosis of the lung were observed. This was reported for all groups of benzoic acid treated animals with a concentration-dependent increase in intensity and incidence.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
0.25 mg/L air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical signs
mortality
Key result
Dose descriptor:
LOAEL
Remarks:
systemic
Effect level:
1.2 mg/L air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical signs
mortality
Key result
Dose descriptor:
LOAEL
Remarks:
Local (pulmonary)
Effect level:
0.025 mg/L air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
histopathology: non-neoplastic

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
0.025 mg/L air
System:
respiratory system: lower respiratory tract
Organ:
lungs
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

Applicant's summary and conclusion

Conclusions:
Inhalation toxicity of benzoic acid was evaluated in rats using fine benzoic acid dust with a mean aerodynamic particle diameter of 4.7 μm (Rop, 1981). Based on these results the RAC opinion concluded on a NOAEL and a LOAEL for systemic toxicity of 0.25 mg/L and 1.2 mg/L, respectively, and a LOAEL of 0.025 mg/L for local pulmonary toxicity.
Executive summary:

Inhalation toxicity of benzoic acid was evaluated in rats using fine benzoic acid dust with a mean aerodynamic particle diameter of 4.7 μm (Rop, 1981). Evaluation of survival, body weight and organ weight demonstrated significant systemic toxicity including 2/20 mortalities at the top dose of 1.2 mg/L. A reddish discharge around the nares was observed at doses ≥ 0.25 mg/L. In addition to systemic toxicity, compoundrelated microscopic lesions consisting of multifocal to generalised inflammatory cell infiltrates and interstitial fibrosis of the lung were observed. This was reported for all groups of benzoic acid treated animals with a concentration-dependent increase in intensity and incidence. The systemic effects observed at higher concentrations differed from those observed after oral exposure at higher concentrations (organ weight decrease, platelet decrease) and are thought to be secondary to local lung toxicity. Because the toxic effects observed in this study are attributed to the physico-chemical properties of these fine low-solubility particles, the study is not considered relevant for the evaluation of human health effects after repeated exposure to fluid benzoic acid formulations used in biocidal applications.

Based on these results the RAC opinion concluded on a NOAEL and a LOAEL for systemic toxicity of 0.25 mg/L and 1.2 mg/L, respectively, and a LOAEL of 0.025 mg/L for pulmonary toxicity.