12-hydroxystearic acid

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for data waiving:

other:

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1970

Materials and methods

Objective of study:

absorption

Principles of method if other than guideline:

In a first 12 week subacute preliminary trial, weanling female rats (3 per group) were fed diets containing 0-20% hydrogenated castor oil. Prior to autopsy, blood samples were taken for hematological analysis. At autopsy,organ weights were recorded and numerous tissues were preserved for microscopic pathological examination. The preliminary trial was repeated in a second test (12 week) but the substance was dissolved in corn oil before being added to the diet.

In the main study of 16 weeks, a total of 90 young albino male rats were segregated into groups of 6 to give the same mean weight per group. Weekly records of individual body weights and food intake by groups were maintained. The diet fed contained either 20% corn oil (control diet), 1% hydrogenated castor oil and 19% corn oil or 10% hydrogenated castor oil and 10% corn oil. After 8 weeks of feeding, half of the groups of rats on hydrogenated castor oil diets were given the corn oil diet until the end of the experiment at 16 weeks. On the fifth week, 3 rats on the 1 and 10% hydrogenated castor oil diets were autopsied. At 8 and 12 weeks, sets of 3 rats on the corn oil diet were also autopsied.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Castor oil, hydrogenated

EC Number:

232-292-2

EC Name:

Castor oil, hydrogenated

Cas Number:

8001-78-3

IUPAC Name:

8001-78-3

Details on test material:

- Name of test material (as cited in study report): Hydrogenated castor oil
- Physical state: solid (granulated powder)
- Composition of test material, percentage of components: 12-hydroxystearic acid: 86.5%; non-oxygenated acids: 10.3%; 12-ketostearic acid: 3.2%

Radiolabelling:

no

Test animals

Species:

rat

Strain:

other: Slonaker substrain of Wistar strain

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 43-83 g (main study). No data reported for the 2 preliminary studies
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: Unchanged in the first feeding trials. Mixed with corn oil in the second feeding trial and the 16 week study

Details on exposure:

PREPARATION OF DOSING SOLUTIONS
- In the first preliminary trial, hydrogenated castor oil was mixed directly into the diets. In the second preliminary trial and in the main study of 16 wk, hydrogenated castor oil was melted and mixed with corn oil, then blended with the diet.
- Mixing appropriate amounts with (Type of food): Purina Laboratory Chow

VEHICLE
- Concentration in vehicle: In the second preliminary study: 1, 5 and 10% hydrogenated castor oil. In the main study: 1 and 10% castor oil, hydrogenated.
- Amount of vehicle (if gavage): In the second preliminary study: 19, 15 and 10% corn oil, respectively. In the main study: 19 and 10% corn oil, respectively.
- Other: After 8 weeks of feeding in the main study half of the groups of rats on the hydrogenated castor oil diets was given the corn oil diet until the end of the experiment

Duration and frequency of treatment / exposure:

The two preliminary trials: 12 weeks
The main study: 16 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
First preliminary trial: 0, 5, 10 and 20%
Second preliminary trial: 0, 1, 5, 10%
Main study: 0, 1 and 10%

No. of animals per sex per dose / concentration:

No data

Control animals:

other: yes, concurrent no treatment in the preliminary trials and concurrent vehicle (castor oil) in the main study

Positive control reference chemical:

No

Details on study design:

- Dose selection rationale: The preliminary trials were conducted for selecting the test doses. The only abnormality noted was a reduced growth rate in the first preliminary trial at the concentrations 10 and 20% hydrogenated castor oil. According to the study, the test susbtance is probably poorly digested because of its high melting point (above 80°C), so poor weight gains may be due to the lower caloric density of the diets containing 10% of the test material. As a check on this premise, the preliminary test was repeated but the test substance was dissolved in corn oil before being added to the diets.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): Blood (in all 3 studies).
- Time and frequency of sampling:
Blood: Before autopsy

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): In the main study: abdominal fat, carcasses lipids and adipose tissue.
- Time, number frequency of sampling and from how many animals (samples pooled):
Abdominal tissue: After 4 weeks 3 rats on 1 % and 10% diet, respectively. At 8 and 12 weeks a set of 3 rats fed corn oil was used.
Lipids: At 8, 12 and 16 weeks lipids from 3 rats were extracted, respectively.
Carcasses lipids: After the rats were autopsied (in duplicate). The extraction was done with ether in a Soxhlet extractor.
- Method type(s) for identification: Silica gel G thin layer chromatographic (TLC) strip and UV.

Results and discussion

Preliminary studies:

First preliminary trial: The only abnormal effect noted was a reduced growth rate in the rats fed diets containing 10 and 20% hydrogenated castor oil. The test substance is probably poorly digested because of its high melting point, so poor body weight gain may be due to the lower caloric density of the diets containing 10% or more of this material.

In the second preliminary trial, were corn oil had been added to each dose, respectively, the growth of rats fed 10% hydrogenated castor oil seemed equivalent to the rats on the other diets. According to the study, the test susbtance is probably poorly digested because of its high melting point (above 80°C), so poor weight gains may be due to the lower caloric density of the diets containing 10% of the test material.

No adverse effects were detected as indicated by organ weights and results of hematological and microscopic pathological examinations.

Main ADME results

Main ADME results 1

Type:

metabolism

Results:

Only 9-14% was digested in rats fed diets without corn oil

Main ADME results 2

Type:

metabolism

Results:

Digestibility ranged between 27-64% in rats fed diets mixed with corn oil (1:3) depending on the level fed

Main ADME results 3

Type:

distribution

Results:

From 4 week old rats fed 1% diet, abdominal fat fatty acids were 0.9% by weight castor oil, hydrogenated-derived hydroxy acids

Main ADME results 4

Type:

distribution

Results:

From 8-16 week old rats fed 1% diet, abdominal fat fatty acids were 0.35% by weight castor oil, hydrogenated-derived hydroxy acids

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Very low absorption of hydrogenated castor oil in rats fed pure diets without corn oil.
The greatest content of hydrogenated castor oil-derived hydroxy acid in lipid was 4.4% in abdominal fat of rats of 4 weeks on the 10% diet. This proportion decreased during the following weeks and at 16 weeks only 2% was detected.

Details on distribution in tissues:

Hydroxystearic acid was deposited in abdominal fats and other body lipids among with its metabolites.
Acids obtained from carcass lipids contained a smaller proportion of hydrogenated castor oil-derived hydroxy acids than did abdominal fatty acids - about 0.28% in the 8-16 week period. Therefore, it appears that there is a greater concentration of hydroxy acid in abdominal fat than in the rest of the body lipids.

Details on excretion:

Not determined

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

From hydroxystearic acid: hydroxypalmitic acid, hydroxymyristic acid, hydroxylauric acid, see Figure 2 under "attached background material".

Any other information on results incl. tables

The percent composition of the hydrogenated castor oil-derived hydroxy fatty acids in rat lipids was approximately:

- 81% 12 -hydroxystearic acid

- 17% 10 -hydroxypalmitic acid

- 1.6% 8 -hydroxymyristic acid

- 0.4% 6 -hydroxylauric acid

According to the caloric availability assay only 9 -14% of the powdered test substance was digested and, consequently, the caloric availability value was only 18% of the value equivalent amount of the corn oil.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: Low absorption
Under the conditions of the study, hydrogenated castor oil was considered to have a low absorption potential in rat.

Executive summary:

A 16 week feeding study was conducted on rat to evaluate the deposition and metabolism of the test substance.

In a 12 week subacute toxicity preliminary trial, weanling female rats were fed diets containing 0-20% test substance. Prior to autopsy, blood samples were taken for hematological study. At autopsy, organ weights were recorded and numerous tissues were preserved for microscopic pathological examination. The test was repeated in a second preliminary trial where the substance was dissolved in corn oil before being added to the diet.

In the main study of 16 weeks, a total of 90 young albino male rats were segregated into groups of 6 to give the same mean weight per group. Weekly records of individual body weights and food intake by groups were maintained. The diet fed contained either 20% corn oil (control diet), 1% hydrogenated castor oil and 19% corn oil or 10% hydrogenated castor oil and 10% corn oil. After 8 weeks of feeding, half of the groups of rats on hydrogenated castor oil diets were given the corn oil diet until the end of the experiment at 16 weeks. On the fifth week, 3 rats on the 1 and 10% hydrogenated castor oil diets were autopsied. At 8 and 12 weeks, sets of 3 rats on the corn oil diet were also autopsied.

For determining the deposition and metabolism of the test substance following tissues were pooled for analysis: abdominal fat, carcass lipids and adipose tissue.

A very low absorption of the test substance was observed in rats fed pure diets without corn oil. The greatest content of the test substance-derived hydroxy acid in lipid was 4.4% hydroxy acids in abdominal fat of rats after 4 weeks on the 10% diet. This proportion decreases during the following weeks and at 16 weeks only 2% was detected.

Furthermore, hydroxystearic acid was deposited in abdominal fats and other body lipids among with its metabolites.

Under the conditions of the study, the test substance was considered to have a low absorption potential in rat.