Registration Dossier

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 guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
Qualifier:
according to
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

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
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