2-Propen-1-one, 3-(dimethylamino)-1-(3-pyridinyl)-

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

26 June 2000 - 24 July 2000

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study has been performed according to OECD guidelines and according to GLP principles.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2000

Report date:

2000

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: EEC Directive 96/54/EEC, B.7 Repeated Dose (28 days) Toxicity (oral), 1996.

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-Dimethylamino-1-(3-pyridinyl)-2-propen-1-one

Cas Number:

55314-16-4

Molecular formula:

C10 H12 N2 O

IUPAC Name:

3-Dimethylamino-1-(3-pyridinyl)-2-propen-1-one

Details on test material:

- Name of test material (as cited in study report): STI571 Y5A
- Substance type: Brown solid
- Physical state: solid
- Analytical purity: >95%
- Lot/batch No.: 0093800007
- Expiration date of the lot/batch: 08 May 2001 (allocated by NOTOX, 1 year after receipt of the test substance)
- Storage condition of test material: In refrigerator in the dark.
- Purity: Not indicated by sponsor; treated as 100% pure
- Stability under storage conditions: Not indicated
- Stability in vehicle: see details on Analytical verification of doses or concentrations.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

(Milli-U)

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

At least 28 days.

Frequency of treatment:

Once daily, at approximately the same time each day, 7 days per week. Animals were dosed up to the day prior to necropsy.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 50, 150 and 1000 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Results and discussion

Effect levels

Dose descriptor:

NOAEL

Effect level:

>= 150 - < 1 000 other: mg/kg/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Toxic effects were only noted at 1000 mg/kg. Rats treated at 50 or 150 mg/kg/day were free of treatment-related findings.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Treatment with STI571 Y5A by daily oral gavage resulted in the death of four males and two females at 1000 mg/kg. Various clinical signs, macroscopic and microscopic findings were noted among these animals, which indicated that the cause of death or moribundity in these rats may be due to poor overall condition and stress as a result of treatment with the test substance.
 
Toxic effects were only noted at 1000 mg/kg, and were most overtly present among males. These effects consisted of reduced body weights, associated with a reduced food intake. Reduced terminal body weights may reflect the decreased weights of several organs, such as the decreased splenic weights of females. In addition, laboratory investigations revealed altered values such as a decreased mean corpuscular volume and increased alanine aminoacyl transferase activities among females. The sole surviving male showed several altered blood parameters. Microscopic examination showed adverse morphologic alterations in several organs at 1000 mg/kg which generally confirmed the macroscopic abnormalities. The microscopic findings were considered indicative of general systemic toxicity and stress effects rather than specific organ toxicity and, again, were mainly noted among males.
 
Rats treated at 50 or 150 mg/kg/day were free of treatment-related findings.
 
From the results presented in this report a definitive No Observed Adverse Effect Level (NOAEL) for STI571 Y5A of 150 mg/kg/day was established.