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Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15 November 1999 to 01 June 2001
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GP study according international guidelines.
according to guideline
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
Limit test:
Crj: CD(SD)
Route of administration:
oral: gavage
corn oil
Details on oral exposure:
Each group received dose preparations containing the carrier only or with 50, 150, or 1,000 mg of test material/kg of body weight/day (mg/kg/day) at a dose volume of 10 mL/kg.
Details on analytical verification of doses or concentrations:
It is not possible to detect Ceraphyl RMT in the vehicle corn oil and for this reason no dose analysis was conducted. Accurate recordings of the amounts of test material used in the preparations are recorded in the data. It is possible to determine with a reasonable level of accuracy that the animals received the correct amount of substance over the course of the study.
Duration of treatment / exposure:
28 days
Frequency of treatment:
7 days/week
Doses / Concentrations:
50, 150, or 1,000 mg/kg/day
actual ingested
No. of animals per sex per dose:
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: No toxicity expected up to 1000 mg/kg/bw
- Animal assignment: Each animal was assigned a temporary number upon arrival. Before initiation of treatment, a microchip identification device was implanted into each animal. After randomization for placement on test, each animal was assigned a permanent number, and the microchip was coded with the permanent number. All data for an animal were recorded under these numbers.
Positive control:
Not applicable
Observations and examinations performed and frequency:
The animals were observed twice daily (a.m. and p.m.) for mortality and moribundity.
Once daily, cageside observations were made for each animal; abnormalfindings were recorded.
Once prior to treatment and weekly during treatment, each animal was removed from its cage and examined for abnormalities and signs of toxicity;
abnormal findings or an indication that the animal appeared normal was recorded.
Expanded Clinical Observations (hand-held and open-field observations and elicited behavior tests) were conducted on all animals once during Week 4: each animal was evaluated during handling, in an open field, and for sensory reactivity to stimuli.
Motor activity of each animal was assessed once during Week 4: the animals were placed into an automated photocell activity recording device for 40 minutes, and activity counts were recorded at 2-minute intervals for a total of 40 minutes.
Body weight and food consumption data were collected weekly during treatment. Blood samples were collected for hematology, coagulation, and clinical chemistry tests from all animals on Day 30.
Sacrifice and pathology:
On Day 30, the animals were anesthetized, weighed, exsanguinated, and necropsied. At necropsy, macroscopic observations were recorded, selected organs were weighed, and selected tissues were collected and preserved. Microscopic examinations were done on tissues fiom each animal in the control and high-dose groups. Macroscopic lesions were also examined microscopically from each animal in the low- and mid-dose groups.
Levene’s test (Levene, H., 1960.“Robust Tests for Equality of Variances,” Contributions to Probability and Statistics, eds.: I. Olkin et al., Ch. 25, pp. 278-292, Stanford University Press: Stanford, California) was done to test for variance homogeneity. In the case of heterogeneity of variance at p ≤ 0.05, transformations were used to stabilize the variance (Conover, W.J. and Iman, R.L., 1981."Rank transformations as a bridge between parametric and nonparametric statistics", Am. Statist., Q: 124-129; Dixon, W.J. and Massey, Jr., F.J., 1969."Introduction to Statistical Analysis", McGraw-Hill, NY, 3rd Ed.). Comparison tests took variance of heterogeneity into consideration.
One-way analysis of variance or ANOVA (Winer, B. J., 1971.“Design and Analysis of Single-Factor Experiments,” Statistical Principles in Experimental Design, Second Ed., Ch. 3, pp. 149-260, McGraw-Hill: NY.) was used to analyze body weights, body weight changes, food consumption, motor activity, grip strength, continuous clinical pathology values, and organ weight data. If the ANOVA was significant, the Dunnett’s t-test (Dunnett, C. W., 1964. “New Tables for Multiple Comparisons with a Control,” Biometrics, 20:482-491) was used for control versus treated group comparisons.Group comparisons (Groups 2 through 4 versus Group 1) were evaluated at the 5.0%, two-tailed probability level. Only data collected on or alter the first day of treatment were analyzed statistically.

Clinical signs:
no effects observed
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: All animals survived to the scheduled sacrifice. There were no test material-related clinical observations throughout the duration of the study. There were no test material-related findings noted during the expanded clinical observations assessed at Week 4.
BODY WEIGHT AND WEIGHT GAIN AND FOOD CONSUMPTION: There were no statistically significant differences in mean body weights, body weight gains, or food consumption.
NEUROBEHAVIOUR: The motor activity of the animals during Week 4 was similar across all groups.
PATHOLOGY: Administration of Ceraphyl RMT at dose levels up to 1,000 mg/kg/day had no apparent effects on clinical pathology test results. There were no test material-related changes for absolute organ weights, organ-to-body weight percentages, organ-to-brain weights ratios, macroscopic findings, or microscopic findings.
Dose descriptor:
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Critical effects observed:
not specified
Administration of Ceraphyl RMT by oral gavage to Crl:CD®(SD)IGS BR rats for 29 days was well-tolerated at doses ranging from 50 to 1,000 mg/kg. There were no test material-related findings that were considered adverse at any dose level. Hence, Ceraphyl RMT should not be classified for repeated dose toxicity.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
1 000 mg/kg bw/day
Study duration:

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
A sub-acute study (28 days) with the target substance supported by a sub-chronic study (90 days) with an analogue substance (Castor Oil).

Justification for classification or non-classification

Not classified.