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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
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:
The analogue approach is used for the hazard assessment of toxicological endpoints for the registration of the target substance trimethylolpropane ricinoleate (CAS 68551-65-5) based on generation of different breakdown/metabolic products, resulting not only in similar physical and biological systems (Scenario 2 of the Read-Across Assessment Framework (RAAF, ECHA, 2015), but also consequently in similar physico-chemical and toxicological properties. The source compounds for read-across are fatty acids, C16-18, esters with pentaerythritol (CAS 85116-93-4) and pentaerythritol ricinoleate (CAS 78-22-8). It is proposed that the different alcohols resulting from ester hydrolysis of the source compounds and the target substance will not result in significant variation in biological effects.
Neither target nor source compounds are classified for mammalian hazardous effects. The use of reliable experimental data, all evaluated as reliable according to Klimisch scores of 1 or 2, to estimate the toxicity of the registered substance is adequate for the purposes of fulfilling the data requirements of registration and classifying potential hazards. Similar grouping into categories has been accepted by other regulatory agencies (U.S. EPA, 2010; U.S. FDA for food notifications). Thus, this read-across approach is adequate for the purposes of risk assessment and classification and labeling.
Cross-reference
Reason / purpose for cross-reference:
read-across source
Reference
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.

Data source

Referenceopen allclose all

Reference Type:
review article or handbook
Title:
Ricinus Communis (Castor) seed oil, hydrogenated castor oil, glyceryl ricinoleate, glyceryl ricinoleate SF, ricinoleic acid, potassium ricinoleate, sodium ricinoleate, zinc ricinoleate, cetyl ricinoleate, ethyl ricinoleate, glycol ricinoleate,
Author:
Johnson Jr., W
Year:
2007
Bibliographic source:
Int. J. Toxicol 26 (Suppl. 3):31–77, 2007
Reference Type:
publication
Title:
The absence of ricinoleic acid from phospholipids of rats fed castor oil
Author:
Stewart WC and Sinclair RG
Year:
1945
Bibliographic source:
Arch Biochemistry 8: 7

Materials and methods

Objective of study:
absorption
excretion
Test guideline
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

Test material

Constituent 1
Chemical structure
Reference substance name:
2,2-bis(hydroxymethyl)butyl (R)-12-hydroxyoleate
EC Number:
266-551-6
EC Name:
2,2-bis(hydroxymethyl)butyl (R)-12-hydroxyoleate
Cas Number:
67025-99-4
Molecular formula:
C24H46O5
IUPAC Name:
2,2-bis(hydroxymethyl)butyl 12-hydroxyoctadec-9-enoate
Constituent 2
Reference substance name:
castor oil fatty acid (non-ricinoleate) mono-ester with trimethylolpropane
Molecular formula:
UVCB - Variable molecularformula and weight
IUPAC Name:
castor oil fatty acid (non-ricinoleate) mono-ester with trimethylolpropane
Constituent 3
Chemical structure
Reference substance name:
Castor oil, ester with glycerol
EC Number:
270-616-4
EC Name:
Castor oil, ester with glycerol
Cas Number:
68459-67-6
Molecular formula:
UVCB - Varied molecular weight and formula
IUPAC Name:
castor oil fatty acid esters with glycerol
Constituent 4
Chemical structure
Reference substance name:
Castor oil
EC Number:
232-293-8
EC Name:
Castor oil
Cas Number:
8001-79-4
Molecular formula:
UVCB
IUPAC Name:
castor oil
Constituent 5
Chemical structure
Reference substance name:
Glycerol
EC Number:
200-289-5
EC Name:
Glycerol
Cas Number:
56-81-5
Molecular formula:
C3H8O3
IUPAC Name:
propane-1,2,3-triol
Constituent 6
Chemical structure
Reference substance name:
Fatty acids, castor-oil
EC Number:
263-060-9
EC Name:
Fatty acids, castor-oil
Cas Number:
61789-44-4
Molecular formula:
UVCB - Varied formula and molecular weight. Mostly C18, some C16 and possibly other carbon chain components
IUPAC Name:
fatty acids, castor oil
Constituent 7
Chemical structure
Reference substance name:
Propylidynetrimethanol
EC Number:
201-074-9
EC Name:
Propylidynetrimethanol
Cas Number:
77-99-6
Molecular formula:
C6H14O3
IUPAC Name:
2-ethyl-2-(hydroxymethyl)propane-1,3-diol
Test material form:
liquid
Radiolabelling:
no

Test animals

Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
Adult rats

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Duration and frequency of treatment / exposure:
daily for 4-6 weeks
Doses / concentrationsopen allclose all
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.

Results and discussion

Preliminary studies:
No evidence of catharsis in rats fed 48.4% castor oil in the diet (stock ration)
Main ADME resultsopen allclose all
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

Toxicokinetic / pharmacokinetic studies

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.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Metabolites are ricinoleic acid and its mono- or diglycerides.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:
Parent castor oil is not absorbed through the GI tract; metabolites are rapidly absorbed.

Any other information on results incl. tables

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

Applicant's summary and conclusion

Conclusions:
Castor oil, a structural analogue, 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. The same processes are expected to take place for the target (registered) substance, trimethylolpropane ricinoloeate, based on similarities between the respective fatty acids and polyols.