Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15 January - 25 June, 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Identification: DC 5067
Description: Clear, light brown liquid
Lot Number: AB 090122
Purity: >99%
Storage conditions: In the original container at room temperature in the dark
Stability under storage conditions: Stab1e
Expiry date: December 1, 1991

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days
Frequency of treatment:
Once daily, approximately the same time each day, 7 days per week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
Dose Levels: 0 (distilled water), 300, 600, 1000 mg/kg b.w./day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
Dose volume: 1.05 (distilled water, 0.32, 0.63, 1.05 mg/kg b.w./day
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes

Results and discussion

Effect levels

Dose descriptor:
NOEL
Effect level:
300 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Oral treatment with DC 5067 resulted in excessive salivation in all treated animals, which was noted from the end of week 1 until termination. However, as this may be attributable to an irritant effect or a bad taste of the test substance, it was considered not to be representativ e of toxicity. statistical significant increases were noted in liver, heart, ki spleen weights after correction for body weight. In the absence corroborrative findings-i,n..clinical pathology or histopathology, toxicological significance of these findings may be considered questionable, although general consistency of effect between males and females should be noted. dney and of any the There were no changes in body weights, food consumption, ophthalmoscopic examination, clinical laboratory investigations, macroscopic examination and microscopic examination that were considered to be an effect of treatment. At the treatment level used a No Observed Effect Level of 300 mg/kg/day was established.

Applicant's summary and conclusion

Conclusions:
From the results Presented in this report a definitive No Observed Effect Level (NOEL) of 300 mg/kg/day was established.
Executive summary:

RATIONALE FOR DOSE LEVEL SELECTION

A 5-day range finding study was performed (with 3 rats/sex/group at dose level.5 Of 300, 600 and 1000 mg/kg/day) to provide a basis for selection of dose levels for a study of longer duration. ~0 differences of biological significance were observed in clinical appearance, body weight, food consumption, macroscopic appearance or liver weights between the treated groups. Based on these observations, a high treatment level of 1000 mg/kg/day was selected for a study of 28 days duration.

METHODOLOGY

In this subacute 28-day toxicity study, DC 5067 was administered daily by gavage to SPF-bred Wistar rats. The study comprised of four 'groups. The number of rats assigned to toxicity testing per group as well as the dose levels administered were as follows:

The number of rats assigned to toxicity testing per group as well as the dose levels administered were as follows:

Total number of animals: 40 (20 males, 20 females), Total number of animals per group: 5 males, 5 females

Dose levels: 0 mg/kg, 300 mg/kg, 600 mg/kg, 1000 mk/kg

FINDINGS

At 300 mg/kg/day: No treatment-related changes noted.

At 600 mg/kg/day: Increased relative liver weights were noted in females and relative spleen weights were noted in males.

At 1000 mg/kg/day: Increased relative heart weights were noted in females only and increased relative liver or spleen weights were noted in males and females.