2-Isobutyryl-3,N-diphenylacrylamide

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD Guideline study under GLP

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Version / remarks:

92/69/EWG, B.7

GLP compliance:

yes

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Details on test material:

- Name of test material (as cited in study report): PD 123408
- Physical state: White Poweder
- Composition of test material, percentage of components: not given
- Purity test date: not given
- Expiration date of the lot/batch: not given

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent, England
- Age at study initiation: 28 to 35 days old
- Weight at study initiation: 136 to 196 g , 13 days after arrival
- Fasting period before study:
- Housing: inside barriered rodent facility
- Diet (e.g. ad libitum): at libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 °C
- Humidity (%): 55%
- Air changes (per hr): at least 15/h
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From:1997-08-20 To:1997-09-30

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility and not toxic

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

HPLC

Duration of treatment / exposure:

Test duration: 28 days

Frequency of treatment:

Dosing regime: 7 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:

Basis:
actual ingested

No. of animals per sex per dose:

Male: 5 animals at 15 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 5 animals at 500 mg/kg bw/day
Female: 5 animals at 15 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 5 animals at 500 mg/kg bw/day

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Preliminary Test
- Post-exposure recovery period in satellite groups: none

Positive control:

NO

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, twice daily

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes, first day, then weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: 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: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 4
- Anaesthetic used for blood collection: Yes (halothane)
- Animals fasted: Yes
- How many animals: all


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 4
- Animals fasted: Yes
- How many animals: all

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

effects observed, treatment-related

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

Clinical observations:
In allen Dosierungen wurde vermehrter Speichelfluß
beobachtet. Die Männchen der hohen Dosierung nahmen im
Vergleich zu den Kontrollen vermindert Körpergewicht zu.

Laboratory findings:
Bei den Weibchen der hohen Dosierung wurden erniedrigte
Werte für Hämatokrit und Hämoglobin nachgewiesen.

Die Männchen der hohen Dosierung zeigten erhöhte
Konzentrationen von Harnstoff und Kreatinin und erniedrigte
Werte für Gesamtprotein.

Effects in organs:
Mikroskopisch wurden in den Nieren der Weibchen der hohen
Dosierung eine erhöhte Inzidenz und Schweregrad einer
Basophilie der Tubuli, interstitielle Nephritis,
Papillenödem und Degeneration der Sammelröhren
nachgewiesen.
Eine Degeneration des Sammelkanalepithels wurde bei einem einzigen Weibchen bei
einer Dosis von 500 mg/kg/Tag beobachtet.

Makroskopische Pathologie: Bei der Nekropsie lagen keine
Befunde vor, die auf die Verabreichung der Prüfsubstanz
zurückzuführen waren.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: original NCD unit is mg/kg/day.

2

Dose descriptor:

NOEL

Effect level:

150 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: original NCD unit is mg/kg/day. overall effects: histopathology

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Classified as: Not classified

Executive summary:

In a 28 days oral administration test with BIBEA groups of 5 males and females were exposed to 0, 15, 150 and 500 mg/kg bw/day by gavage with corn oil as the vehicle. There were no teatment-related signs and no animals died. Overall, males receiving 500 mg/kg bw/day geined less weight than the controls. The food conversion efficiency for males receiving 500 mg/kgbw/day was slightly reduced. No significant chamnges in cellularity or chemical composition of the blood. Organ weights and macroscopic pathology showed no treatment related findings. The microscopic examination of the kidneys showed changes, comprising basophilic cortical tubules, interstitial nephritis, papillary oedema and degeneration of collecting duct epithelium in the high dose group. The test produced evidence of a slight general toxicity in males and mild renal toxicity in females at 500 mg/kg bw.

The NOAEL and the NOEL as identified by this study were 150 mg/kg bw/day.