Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February 2019 to May 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-benzoylbenzoic acid
EC Number:
201-612-2
EC Name:
2-benzoylbenzoic acid
Cas Number:
85-52-9
Molecular formula:
C14H10O3
IUPAC Name:
2-benzoylbenzoic acid
Specific details on test material used for the study:
Test item name: 2-Benzoylbenzoic acid
CAS Number 85-52-9
EC Number 201-612-2

Test animals

Species:
rat
Strain:
Wistar
Remarks:
CRL:WI Wistar
Details on species / strain selection:
Test animals obtained from Charles River Laboratories
Sex:
male/female
Details on test animals or test system and environmental conditions:
Environmental Conditions:
Temperature: 18 to 24°C.
Humidity: 40 to 70%.
Light Cycle: 12-hours light and 12-hours dark (may be interrupted
for designated procedures).
Ventilation: At least 10 air changes per hour.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
Trial preparations were performed to select the suitable vehicle and to establish a suitable formulation procedure. These trials were not performed as part of this study and these preparations were not used for dosing. Raw data of these trials will be retained by the Test Facility.

Test item dosing formulations (w/w) was homogenized to visually acceptable levels at appropriate concentrations to meet dose level requirements. The dosing formulations were prepared daily as a suspension and dosed within 6 hours after adding the vehicle to the test item.

Test item dosing formulations will be kept at room temperature until dosing. If practically possible, the dosing formulations and vehicle will be continuously stirred until and during dosing. Adjustment will be made for specific gravity of the vehicle. No correction will be made for the purity/composition of the test item.

Any residual volumes were discarded.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose formulation samples were collected as per the study protocol and guidelines.
Additional samples may be collected and analyzed at the discretion of the Study Director.
Duration of treatment / exposure:
28 days
Frequency of treatment:
once daily, 7 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
No. of animals per sex per dose:
6 per sex per group
Control animals:
yes, concurrent no treatment
Details on study design:
[complete control animals drop down above]
[copy paste study design section of study report, or complete items below - make sure copy pasted information addresses all items]
- Dose selection rationale:
- Rationale for animal assignment (if not random):
- Fasting period before blood sampling for clinical biochemistry:
- Rationale for selecting satellite groups:
- Post-exposure recovery period in satellite groups:
- Section schedule rationale (if not random):
- Other:- Dose selection rationale:
- Rationale for animal assignment (if not random):
- Rationale for selecting satellite groups:
- Post-exposure recovery period in satellite groups:
- Section schedule rationale (if not random):

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD EFFICIENCY: Not specified

HAEMATOLOGY: Yes

CLINICAL CHEMISTRY: Yes

URINALYSIS: Yes

THYROID HORMONE: Yes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes
Statistics:
Provantis v. 9

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Cholesterol (mmol/L), Calcuim (mmol/L), total protein (g/L), albumin (g/L) and ALT/GPT (U/L) showed statistical significance in males.

Creatinine (umol/L) decrease, calcium increase (mmol/L) and total protein (g/L) increase showed statistical significance in females.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Increase in urine volume in males. No statistical significance in females.
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
not specified

Effect levels

Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: clinical signs, functional observations, body weights, food consumption, clinical pathology, macroscopy, organ weights, and histopathology.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Please see tables (attached).

Applicant's summary and conclusion

Conclusions:
The NOAEL of the test item has been determined to be 150 mg/kg bw/day.
Executive summary:

The final version of this OECD 422 study has not yet been received.  Once the final report is received, the dataset will be updated accordingly, and the dossier will be submitted as a spontaneous update.

Interim results however have been issued by the contracted laboratory and as much information as possible has been entered to create the robust study summary.

The study has been performed in accordance with the standardised OECD 422 guidelines, under GLP conditions.

The test animals (rats) were dosed with the test item orally, via gavage at the following concentrations: 0, 50, 150 and 500 mg/kg bw/day.

The effects observed were increase in urine volumes, increase in kidney and liver weights, increase in food consumption, increase in thyroid weights (males only). There were also some clinical signs at the top dose (thin fur and noisy respirartion).

In conclusion, the NOAEL of the test item has been determined to be 150 mg/kg bw/day.