1,3-bis(3-methyl-2,5-dioxo-1H-pyrrolinylmethyl)benzene

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

other: subacute

Type of information:

experimental study

Adequacy of study:

key study

Study period:

October-November 1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well conducted study according to GLP

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1994

Report date:

1994

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: MHW-MITI (1986)

Deviations:

not specified

GLP compliance:

yes

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Details on test material:

Batch no: 910312 (see CoA attached)
Purity: 88±3% (m/m)
Other: mono-citracon-mono-itaconimide isomer: 6.5±2% (m/m)
Unknown: 5.5±2% (m/m)

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

maize oil

Details on oral exposure:

Method of administration: gavage

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

Test duration: 28 days

Frequency of treatment:

Dosing regime: daily

Doses / concentrations

Remarks:

Doses / Concentrations:
10, 50, 200 mg/kg bw
Basis:
other: nominal in maize oil

No. of animals per sex per dose:

Male: 10 animals at 0 mg/kg bw/day Male: 5 animals at 10 mg/kg bw/day Male: 5 animals at 50 mg/kg bw/day Male: 10 animals at 200 mg/kg bw/day
Female: 10 animals at 0 mg/kg bw/day Female: 5 animals at 10 mg/kg bw/day Female: 5 animals at 50 mg/kg bw/day Female: 10 animals at 200 mg/kg bw/day
5 animals/sex of the control and high dose group were treated for 28 days and then kept for a 14-day recovery period.

Control animals:

yes, concurrent no treatment

Results and discussion

Results of examinations

Details on results:

Clinical observations: Four male and one female animal from the high dose group were foud dead or humanely killed. Ante mortem sighns were
rales, gasping and abdominal distension, hunched posture and pilo-erection. The surviving animals of the high dose group showed salivation,
ungroomed appearance and pilo-erection. The mid-dose animals showed salivation and isolated incidences of pilo-erection, hunched posture and
ungroomed fur. Of the low dose group three rats showed salivation.
Laboratory findings: Haematology was unaffected. In the high dose group aspartate asmino-tranferase activity and plasma urea concentration
were slightly higher in the animals killed at day 28. These differences were not observed at the end of the 2-week reversibility period.
Effects in organs: No treatment related macropathological effects observed.
Histopathology: In the rats from the high dose level, hyperkeratosis and acanthosis in the keratinised region of the stomach were seen. Although the findings were still evident in animals 2 weeks after treatment had ceased, their frequency was much reduced.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

2

Dose descriptor:

NOEL

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Clear toxicity including mortality was observed at 200 mg/kg bw, limited clinical signs were observed at 50 mg/kg bw, whereas no significant effects were seen at 10 mg/kg bw. As such the NOAEL is 50 mg/kg bw, and the NOEL 10 mg/kg bw.
Classified as: Not classified