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Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
metabolism
Qualifier:
no guideline available
Principles of method if other than guideline:
in vitro metabolism using radiolabelled esters
GLP compliance:
no
Specific details on test material used for the study:
Radiolabelled product synthesized in house. TLC showed product to be homogeneous.
Radiolabelling:
yes
Remarks:
Sp activity of 4200 cpm/ µmole
Species:
rat
Strain:
other: not specified
Sex:
not specified
Route of administration:
other: in vitro
Type:
metabolism
Results:
Hydrolysis primarily by rat nonspecific lipase
Details on absorption:
No data
Details on distribution in tissues:
No data
Details on excretion:
No data
Metabolites identified:
yes
Remarks:
tetraester, triester, diester, monoester, and erythritol
Details on metabolites:
Erythritol tetraoleate was hydrolysed by nonspecific lipase (from rat), confirming is action only on esters of primary alcohols. The initial digestion product was 1,2,3-trioleate. Lipase then removes a fatty acid from the triester, forming erythritol-2,3-dioleate. The digestion continues in a stepwise manner from tetraester to triester to diester to monoester to erythritol. Hydrolysis of the tri- and diesters is rapid; the rate-limiting step is the hydrolysis of the tetraester.
Conclusions:
Hydrolysis of pentaerythritol tetraoleate was demonstrated in vitro by the combined action of rat pancreatic lipase and nonspecific lipase. The digestion occurs in a stepwise manner from tetraester to triester to diester to monoester to erythritol.
Endpoint:
basic toxicokinetics in vivo
Type of information:
other: Review of experimental data
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Scientifically reliable and peer reviewed by CIR Expert Panel, USA
Justification for type of information:
Judged to be scientifically reliable and appropriate for risk assessment by the Expert Panel of dermatologists and scientists at the Cosmetics Ingredient Review, Washington, DC., U.S.A
Objective of study:
absorption
excretion
Qualifier:
no guideline followed
Principles of method if other than guideline:
in vivo dietary feeding/metabolism study of castor oil in rats
GLP compliance:
no
Remarks:
predates development of GLP
Specific details on test material used for the study:
no data
Radiolabelling:
no
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
Adult rats
Route of administration:
oral: feed
Vehicle:
not specified
Duration and frequency of treatment / exposure:
daily for 4-6 weeks
Dose / conc.:
0 other: %
Dose / conc.:
48.4 other: %
No. of animals per sex per dose / concentration:
not specified. ≥ 3.
Control animals:
not specified
Details on study design:
Adult rats received a diet containing 48.4% castor oil for 4-6 weeks. Control rats received stock ration only. Feces were collected from 3 rats on the castor oil diet. At the end of the feeding period, excised organs/tissues were ground thoroughly and samples of phospholipid fatty acids were obtained from the liver, small intestine and muscle; glyceride fatty acids were obstained from the liver and fat depots.
Preliminary studies:
No evidence of catharsis in rats fed 48.4% castor oil in the diet (stock ration)
Type:
absorption
Results:
Metabolites but not parent substance are rapidly absorbed and found in glycerides and cholesterol esters of the fat depots.
Type:
excretion
Results:
Fatty acids were excreted
Details on absorption:
Ricinoleic acid was absorbed from dietary castor oil and was found as a component acid (up to 7%) of the fatty acids in glycerides in carcass fat depots. The feeding of castor oil did not lead to the appearance of significant amounts of ricinoleic acid in glycerides in the liver, nor in phospholipids of any organ tested (liver, small intestine and skeletal muscle). Total body fat in these three animals was also determined, and it was calculated that 1-2% of absorbed ricinoleic acid was deposited in the fat depots.
Details on distribution in tissues:
Metabolites (diglycerides and ricinoleic acid) are absorbed, distributed and measurable in fat depots.
Details on excretion:
The fatty acids excreted by each of three rats amount to 2.1, 2.2 and 3.6% of those ingested. It is assumed that this is in the animals fed castor oil and refers to ricinoleic acid.
Metabolites identified:
yes
Details on metabolites:
Metabolites are ricinoleic acid and its mono- or diglycerides.
Bioaccessibility (or Bioavailability) testing results:
Parent castor oil is not absorbed through the GI tract; metabolites are rapidly absorbed.

Ricinoleic Acid Content of Phospholipids

 

Ricinoleic Acid content (%) in Control-fed rats

No. of analyses

Ricinoleic Acid content (%) in Castor Oil-fed rats

 

No. of analyses

Liver

1.7 ± 1.1

7

1.3 ± 0.6

9

Small intestine

6.0 ± 4.4

4

4.9 ± 1.7

8

Skeletal muscle

4.0 ± 1.7

7

3.6 ± 2.9

8

Ricinoleic Acid Content of Glycerides and Cholesterol Esters in Fat Depots

 

Ricinoleic Acid content (%) in Control-fed rats

No. of analyses

Ricinoleic Acid content (%) in Castor Oil-fed rats

 

No. of analyses

Liver

5.6 ± 4.1

5

7.2 ± 2.4

8

Carcass Fat Depots

0.5 ± 0.5

7

6.8 ± 4.2

11

Conclusions:
Castor oil is rapidly hydrolysed by lipases into ricinoleic acid and di- and mono-glycerides, which are absorbed. Ricinoleic acid is found in carcass fat depots (comprising approximately 7% of the total fatty acid content) This fatty acid was not found in hepatic glycerides or in phospholipids of the liver, small intestine or skeletal muscle. These metabolites are rapidly processed and excreted or stored.

Description of key information

PE esters of castor oil are not absorbed orally, but are rapidly hydrolysed, processed in a similar manner as are triglycerides, and excreted or stored in fat.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
10

Additional information

Castor oil PE esters are poorly water soluble and may partition to lipid. They are not readily absorbed after oral exposure but are rapidly hydrolysed by lipases into ricinoleic acid and di- and mono-glycerides, which are absorbed. Parent substance is not absorbed by the oral, dermal or inhalation routes. The metabolite ricinoleic acid can be found in carcass fat depots (comprising approximately 7% of the total fatty acid content). This fatty acid was not found in hepatic glycerides or in phospholipids of the liver, small intestine or skeletal muscle. These metabolites are rapidly processed and excreted or stored. The polyols are not highly absorbed, but primarily excreted in urine unchanged.  PE, as well as TMP and glycerol, have low degrees of toxicity (U.S. EPA, 2010).

In a review by the Cosmetic Ingredient Review (CIR, Becker, et al., 2015) the pentaerythrityl tetraesters are not bioavailable by the dermal route. A study of fatty acids, C5 -9, penterythrityl tetraesters was reported to display 2 -6% skin absorption after repeated dose application in rats.