Registration Dossier

Administrative data

Description of key information

The NOEL was determined to be 500 mg/kg bw in a chronic feeding study in rats.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Publication includes a well documented study summary. For justification of read across see section 13.
Qualifier:
no guideline followed
Principles of method if other than guideline:
4-generation study
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Farbwerke Bayer (Elberfeld)
- Weight at study initiation: 40-50 g
- Diet: during the first 8 weeks the rats were fed according to the pair-feeding method, afterwards food was available ad libitum
- Water: ad libitum

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The applied doses were analytically measured every 6 weeks.
Duration of treatment / exposure:
The first and second generations were exposed lifelong, the third generation was exposed until breeding.
Frequency of treatment:
During the first 8 weeks the rats were fed according to the pair-feeding method, afterwards food was available ad libitum.
Remarks:
Doses / Concentrations:
0, 0.5, 1 %,, corresponding to ca. 0, 75, 150 mg/kg bw/d
Basis:
nominal in diet
No. of animals per sex per dose:
20
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: no data
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: No data

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (3rd generation)
HISTOPATHOLOGY: Yes (3rd generation)
Other examinations:
no data
Statistics:
no data
Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
liver weight inreases were observed in females during lactation (caused by weigth increase and variation in litter size in the 3rd generation)
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Details on results:
ORGAN WEIGHTS
liver weight inreases were observed in females during lactation (caused by weigth increase and variation in litter size in the 3rd generation)
Dose descriptor:
NOEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: An intake of 150 mg (1 %) benzoic acid per day per rat and a bodyweigth of 300 g per rat were assumed.
Critical effects observed:
not specified
Conclusions:
Rats were exposed to 0.5 and 1 % benzoic acid in a chronic feeding study. 1 % benzoic acid was equivalent to 500 mg/kg bw/day. As no effects were observed in any of the four generations, the NOEL was determined to be 500 mg/kg bw.
Executive summary:

Rats were exposed to 0.5 and 1 % benzoic acid in two groups of 20 male and 20 female rats in a chronic feeding study. 1 % benzoic acid in the food is equivalent to 500 mg/kg bw/day. The negative control group 1 consisted of the same amount of animals and received untreated food. The first two generations were treated lifelong, the 3rd generation was treated for 16 weeks and the 4th generation until breeding. No effects were observed in any of the generations except for a liver weight increase in the females of the 3rd generation, but this increase was not considered to be caused by the treatment. On the basis of these results the NOEL for benzoic acid was concluded to be 500 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
old publication on a study using a read across substance but sufficient for assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

As no study on ethyl benzoate was available on this endpoint, a study conducted with benzoic acid as a suitable read across substance was used. Rats were exposed to 0.5 and 1 % benzoic acid in two groups of 20 male and 20 female rats in a chronic feeding study. 1 % benzoic acid in the food is equivalent to 500 mg/kg bw/day. The negative control group 1 consisted of the same amount of animals and received untreated food. The first two generations were treated lifelong, the 3rd generation was treated for 16 weeks and the 4th generation until breeding. No effects were observed in any of the generations except for a liver weight increase in the females of the 3rd generation, but this increase was not considered to be caused by the treatment. On the basis of these results the NOEL for benzoic acid was concluded to be 500 mg/kg bw.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
only one study available

Justification for classification or non-classification

The available data did not indicate a repeated dose toxicity of the test substance. On the basis of these data the substance is not considered to be classified for repeated dose toxicity under Directive 67/548/EEC (DSD) or under Regulation (EC) No 1272/2008 (CLP).