2-(m-benzoylphenyl)propionitrile

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Start of experimental phase: 9 October 2008 - End of experimental phase: 30 October 2008

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study according to international guideline

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: The Rules governing Medicinal Products in the European Community, Vol. 3B (1998), as revised

GLP compliance:

yes

Test type:

acute toxic class method

Test material

Test material information

Constituent 1

Reference substance name:

2-(m-benzoylphenyl)propionitrile

EC Number:

255-982-5

EC Name:

2-(m-benzoylphenyl)propionitrile

Cas Number:

42872-30-0

Molecular formula:

C16H13NO

IUPAC Name:

2-(3-benzoylphenyl)propanenitrile

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Name : KETOPROFEN/BPPN
Batch number : F-CHN-080080-01
Expiry date : 12 August 2009
Description (by the Sponsor) : Solid, off white
Description at first use : Powder, off white/cream
Storage at RTC : +4°C, protected from light
RTC reference number : 11416
Test item characterisation : Not undertaken at the testing facility. The determination of the identity, strength, purity, composition, stability and method of synthesis and/or derivation of the test item was the responsibility of the Sponsor.
Sample archiving : Retained within the RTC archives for a period of 10 years prior to disposal.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

Animal supply and acclimatisation
Species and strain : Rat, Hsd: Sprague Dawley SD
Number and sex : Females (nulliparous and non-pregnant)
Age and weight range (at order): 6 to 7 weeks old, 150 to 174 grams
Supplier : Harlan Italy S.r.l., 33049 San Pietro al Natisone (UD), Italy
Breeder : Harlan Italy S.r.l., 33049 San Pietro al Natisone (UD), Italy
Date of arrival : two different arrivals on 25 September and 9 October 2008
Weight range at arrival : 150.3 to 180.0 grams and 154.7 to 170.1 grams
Acclimatisation period : At least 5 days
Veterinary health check : after arrival

Caging
No. of animals/cage : 3 during the study; up to 5 during acclimatisation
Housing : Polycarbonate cages measuring 42.5x26.6x18 cm (step 1 and 2) or 59x38.5x20 cm (step 3), with stainless steel mesh lid and floor.
Cage tray control : Daily inspected and changed as necessary (at least 3 times/week)

Water and diet
Water : drinking water supplied to each cage via a water bottle
Water supply : ad libitum
Diet : 4 RF 18 (Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI) Italy)
Diet supply : ad libitum throughout the study except for dosing procedure.

Housing conditions (parameters set)
Room lighting: : Artificial (fluorescent tubes), daily light/dark cycle of 12/12 hours
Air changes: : Approximately 15 to 25 air changes per hour
Temperature range: : 22°C ± 2°C
Relative humidity range: : 55% ± 15%
Actual conditions were monitored and recorded, and records retained. No relevant deviations occurred.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Remarks:

Concentration : 30 and 200 mg/ml

Details on oral exposure:

Dosing
Frequency of treatment : Once only, on the day of dosing (Day 1).
Fasting procedure : Overnight prior to dosing (Day –1) up to 4 hours after dosing.
Dose calculation : Dose volume of 10 ml/kg of body weight for each animal.
Dosing method : By gavage, using a rubber catheter attached to a graded syringe.

Doses:

Since information available suggested a possible mortality at the dose level of 2000 mg/kg, a first sub-group of 3 female animals was dosed at a level of 300 mg/kg (Step 1). Mortality did not occur. A second sub-group, similarly composed, was then dosed at the same dose level (step 2). No mortality occurred. Consequently, a first subgroup of 3 females was dosed at 2000 mg/kg. Since mortality occurred in the three animals, no further doses were investigated since the objective of the study had been achieved.

No. of animals per sex per dose:

3 female animals/subgroup

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: mortality and morbidity: twice daily; clinical signs: day of dosing (on dosing, approximately 0.5, 2 and 4h after dosing), daily thereafter (14 days); body weight: allocation (day-1), days 1,2,8 and 15.
- Necropsy of survivors performed: yes

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed in the female animals initially dosed at 300 mg/kg (steps 1 and 2).
Mortality occurred in the three female animals subsequently dosed at 2000 mg/kg (step 3).

Clinical signs:

other: At 300 mg/kg bw, reduced activity, piloerection, hunched posture and semiclosed eyes were recorded on the day of dosing. The 3 female animals of step 1 showed piloerection on Day 2, recovery was completed by Day 3. In the 3 females of step 2 recovery occu

Gross pathology:

No abnormalities were observed at necropsy examination performed on all of the animals dosed at 300 mg/kg (steps 1 and 2) at the end of the observation period.
No abnormalities were recorded at necropsy examination in the two animals dosed at 2000 mg/kg and found dead on Day 2.
In the third animal dosed at the same dose level and found dead on Day 3, abnormal contents (dark, mucoid) were detected in the stomach, jejunum and ileum.
External abnormalities were limited to yellow staining in the urogenital region and brown staining on the muzzle.

Applicant's summary and conclusion

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information H302: Harmful if swallowed. Criteria used for interpretation of results: EU

Conclusions:

These results indicate that the test item, KETOPROFEN/BPPN, has a toxic effect on the rat following oral administration of a single dose at a level of 2000 mg/kg. The lack of mortality demonstrates the LD50 to be greater than 300 mg/kg body weight.