Ricinoleyl monomaleate triglyceride

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

April to July 1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Studies performed and report issued and peer-reviewed as part of the National Toxicology Program under auspicion of U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1992

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Details on test material:

Castor Oil

Test animals

Species:

other: rat and mouse

Strain:

other: F344/N rats; B6C3F1 mice

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test Animals:
Source: Simonsen Laboratories, Gilroy, CA
Method of Animal Distribution: Animals weight-randomized into groups by sex, assigned to cages, and cages assigned to dose groups.
Diet: NIH 07; available ad libitum
Size of Study Groups: 10 males and 10 females of each species. Rats were housed 5 per cage, and mice were individually caged.
Time Held Before Study: Rats 14 d, mice 15 d
Age When Placed on Study: 6 wk
Type and Frequency of Observation: Observed 2 X d, weighed initially and 1 x wk thereafter.
Age When Killed: 19 wk
Animal Room Environment:
Temperature: 68-76°F;
Relative humidity: 42-72%;
Fluorescent light 12 h/d;
Air-changes: 10 room air changes/h

Administration / exposure

Route of administration:

oral: feed

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The stability of the study material during the toxicology studies was monitored by determination of peroxide content and by high performance liquid chromatography. The homogeneity of castor oil in feed at 10% (100 mg/g) was determined by gravimetric analysis, and blends at 0.5% (5 mg/g) were determined by HPLC analysis. Periodic analysis of the castor oil-formulated diets was conducted by HPLC at the study and analytical chemistry laboratories. Three complete sets of formulated diet mixtures were analyzed by either the study laboratory or the analytical laboratory during the 13-week studies.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.62, 1.25, 2.5, 5.0, and 10.0% in feed
Basis:
nominal in diet

No. of animals per sex per dose:

10

Control animals:

yes, plain diet

Examinations

Observations and examinations performed and frequency:

Observed twice per day, weighed initially and once per week thereafter.

Sacrifice and pathology:

Necropsy and Histologic Examinations:
The following tissues were routinely processed for preparation of histologic sections and microscopic examination: adrenal glands, brain, cecum, colon, duodenum, epididymis/seminal vesicles/prostate/testes or ovaries/uterus, esophagus, eyes (if grossly abnormal), femur (including marrow), heart, ileum, jejunum, kidneys, liver, lungs and mainstem bronchi, mammary gland, mandibular and mesenteric lymph nodes, nasal cavity and turbinates, pancreas, parathyroid glands, pituitary gland, preputial or clitoral glands, rectum, salivary glands, skin, spinal cord and sciatic nerve (if neurologic signs present), spleen, forestomach and glandular stomach, thymus, thyroid gland, trachea, urinary bladder, zymbal glands, and all gross lesions and tissue masses including regional lymph nodes.
A complete histopathologic examination was conducted on all rats and mice from the control and 10% dose groups. Liver was examined from male rats in all other dose groups, and histologic sections of gross lesions were examined from all rats.

Statistics:

Body weight and organ weight data were statistically analyzed within each sex by one-way Analysis of Variance tests, followed by Dunnett's t-test if pair-wise comparisons were indicated (p < 0.05).

Results and discussion

Results of examinations

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:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

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:

Rats: for male rats, a slight decrease in MCHC & statistically significant decrease in MCV in the 10% group & in MCH at 5% and 10%; increase in platelets at 1.25, 5, and 10 %. For female rats only a statistically significant decrease in reticulocyte counts at 0.62 or 10 % (day 5). Further, a dose-related increase in the activity of serum alkaline phosphatase at days 5, 21 and 90, and an increase of total bile acids among males only at days 5 and 21 (10%). None of the changes observed was considered biologically significant.
Mice: Increased liver weights in male and female mice and increased kidney weights in female mice receiving diets containing 5% or 10% castor oil. Using light microscopy, it was determined that there were no morphologic changes associated with the slight differences between groups in organ weights. Histopathologic examination revealed an absence of compound-related lesions in any organs or tissues of mice exposed to castor oil in the diet.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

5 800 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

10% in feed for 90 days

Sex:

male

Basis for effect level:

other: Rats

2

Dose descriptor:

NOAEL

Effect level:

5 725 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

10% in feed for 90 days

Sex:

female

Basis for effect level:

other: Rats

3

Dose descriptor:

NOAEL

Effect level:

15 000 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

10%

Sex:

male

Basis for effect level:

other: Mice

4

Dose descriptor:

NOAEL

Effect level:

16 800 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

10% in feed for 90 days

Sex:

female

Basis for effect level:

other: Mice

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

The results of the analyses for all dose mixtures given to the animals ranged from 97% to 106% of the target concentrations.

Applicant's summary and conclusion

Conclusions:

No significant adverse effects of castor oil administration were noted in these studies.

Executive summary:

Castor oil is a natural oil derived from the seeds of the castor bean, Ricinus communis. It is comprised largely of triglycerides with a high ricinolin content. Toxicity studies with castor oil were performed by incorporating the material at concentrations as high as 10% in diets given to F344/N rats and B6C3F1 mice of both sexes for 13 weeks. Genetic toxicity studies also were performed and were negative for mutation induction in Salmonella typhimurium, for induction of sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, and for induction of micronuclei in the peripheral blood erythrocytes of mice evaluated at the end of the 13-week studies.

Exposure to castor oil at dietary concentrations as high as 10% in 13-week studies did not affect survival or body weight gains of rats or mice (10 per sex and dose). There were no biologically significant effects noted in hematologic analyses in rats. Mild increases in total bile acids and in serum alkaline phosphatase were noted at various times during the studies in rats receiving the higher dietary concentrations of castor oil. Liver weights were increased in male rats receiving the 10% dietary concentration and in male and female mice receiving diets containing 5% or 10% castor oil. However, there were no histopathologic lesions associated with these liver changes, nor were there any compound-related morphologic changes in any organ in rats or mice. No significant changes were noted in a screening for male reproductive endpoints, including sperm count and motility, and no changes were observed in the length of estrous cycles of rats or mice given diets containing castor oil. Thus, no significant adverse effects of castor oil administration were noted in these studies.