Ricinoleyl monomaleate triglyceride

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GP study according international guidelines.

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

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

Remarks:

Doses / Concentrations:
50, 150, or 1,000 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

5

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.

Statistics:

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

Mortality:

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:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Critical effects observed:

not specified

Conclusions:

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:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

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.