α-d-Glucopyranoside, β-d-fructofuranosyl, benzoate

Repeated dose toxicity: inhalation

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

Test material information

Constituent 1

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 / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/L air

Remarks:

Controls

Doses / concentrations 2

Dose / conc.:

0.025 mg/L air

Doses / concentrations 3

Dose / conc.:

0.25 mg/L air

Doses / concentrations 4

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

1

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

2

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

3

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.