Trans-esterification product of castor oil and 2-ethyl-2-(hydroxymethyl)propane-1,3-diol

Basic toxicokinetics

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

Reference

Reference 1

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 2

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

Test material information

Constituent 1

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

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

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

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

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

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 / concentrations

Doses / concentrations 1

Dose / conc.:

0 other: %

Doses / concentrations 2

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 results

Main ADME results 1

Type:

absorption

Results:

Metabolites but not parent substance are rapidly absorbed and found in glycerides and cholesterol esters of the fat depots.

Main ADME results 2

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.