Glycerides, castor-oil mono-, di- and tri-

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No experimental data on absorption, metabolism, distribution and elimination are available for the substance. The available data on read-across substance CAS 8001-79-4 is summarized in (Cosmetic ingredient review 2004). Based on this information, the structures and the physico-chemical properties, and the toxicological data of the substance itself the toxicokinetic behaviour can be evaluated.

 

Absorption

Oral route:

Although a smaller molecular weight, especially below 500 is favourable for oral absorption, the size of the larger tri-glycerides is below 1000 g/mol, which is considered the threshold for unfavourable absorption (ECHA guidance R7c. 2017). Therefore, based on the molecular size, absorption of the mono- di and-tri glycerides might be possible although the absorption of the mono- glyceride (molecular weight of 372.5 g/mol) is expected to be more favourable compared to the di (560.9 g/mol) and tri-glycerides (933.4 g/mol). The low water solubility (32 mg/mL for the substance) and relatively lipophilic nature (LogKow of 4.5 for the substance) of the target and source substances might however limit the uptake in the gut. Nevertheless, data on CAS 8001-79-4 (tri-glyceride) indicates that this substance is efficiently taken up (ECHA guidance R7c. 2017), which implies that even the largest component of the substance is bioavailable via de oral route.

Data on CAS 8001-79-4 indicates that enzymatic hydrolysis in the small intestine results in the release of glycerol and ricinoleid acid (see section on metabolism), which might be the actual compounds taken up (Cosmetic ingredient review 2004 [Thompson 1980]). Assuming comparable hydrolysis, this intestinal metabolism results in the uptake of identical components when the substance is administered via the oral route. 

The absorption of the test substance itself could be justified by information presented in the screening for reproductive / developmental toxicity study (OECD 422) which was performed on rats via the oral route (gavage) (BASF, 2018). However, as treatment-related effects are not observed in this study, actual absorption cannot be confirmed.

Dermal route:

The molecular weight of the mono- di and tri-glycerides are all above 100 g/mol which is considered as the upper limit for favourable dermal absorption. The di- and tri-glycerides are unlikely to be taken up via the skin since a molecular weight above 500 is considered to be too large for dermal absorption. In addition, the log Kow and limited water solubility are not in favour of dermal absorption (ECHA guidance R7c. 2017). In the available acute dermal toxicity data on the RA substance with CAS91744-44-4no systemic effects were observed, thus based on these data no conclusion can be drawn on the dermal bioavailability.

Inhalation route:

Based on the physical appearance (viscous liquid), the high boiling point (313 °C for CAS 8001-79-4) and low vapour pressure (≤ 0.2 Pa for CAS 91744-44-4), exposure via the respiratory tract is unlikely. In addition, the low water solubility indicates that the substance may be retained within the mucus (ECHA guidance R7c. 2017).

 

Distribution

The low water solubility and relatively high molecular weight may restrict distribution via the water channels. In addition, the log Kow of the substance (3.8 to 4.5) suggests that it is able to pass through biological cell membranes and does not exclude bioaccumulation. However, efficient metabolism (see next section) makes bioaccumulation unlikely. This assumption is confirmed by feeding studies with CAS 8001-79-4 in rats (48.4% in diet for four to six weeks), it was concluded that there was no significant amounts of ricinoleic acid in phospholipids of the small intestine, liver, and skeletal muscle, nor in glycerides of the liver (Cosmetic ingredient review 2004[Stewart and Sinclair, 1945]). In addition, analysis of total body fat in these animals revealed that 1 to 2% of absorbed fraction was deposited. Based on these findings it was concluded that ricinoleic acid is rapidly metabolized. In a more recent feeding study, ricinoleic acid was present in perirenal adipose tissue lipids, but not in the serum or hepatic lipids (Cosmetic ingredient review 2004[Ihara-Watanabe et al. (1999)]).

 

Metabolism and excretion

The major metabolic reaction is the hydrolysis of the ester bonds. Data on CAS 8001-79-4 shows metabolism to ricinoleic acid by pancreatic lipase (Cosmetic ingredient review 2004[Gaginella and Bass, 1978]) and it was reported that this substance is hydrolyzed in the small intestine by pancreatic enzymes, leading to the release of glycerol and ricinoleic acid (Cosmetic ingredient review 2004[Thompson (1980)]. This implies that the absorbed substances areglycerol and ricinoleic acid instead of the castor oil glycerides.In a different study it was concluded that the released ricinoleic acid was subsequentlyrapidlymetabolized(Cosmetic ingredient review 2004[Stewartand Sinclair, 1945]).Two studies on CAS 8001-79-4, at dose levels of 10 and48.4% in rat diet,showed that the amount of excreted fatty acids is between 0.5 and 3% of the ingested fraction (Cosmetic ingredient review 2004[Stewartand Sinclair, 1945; Ihara-Watanabe et al. (1999)]). In a different studyacorrelation between the dose administered and the percentage of ricinoleic acid in the faeces was reported which indicates that greater absorption takes place at the lower dose.This study also detected aconsiderablefraction of hydroxystearic acid in faeces, which might be explained by hydrogenation of ricinoleic acid in the gut lumen by intestinal bacteria (Cosmetic ingredient review 2004[(Watson and Gordon, 1962)]). 

Metabolic processes are, based on the structural similarity, considered to be similar for the substance.

 

Theoretically, based on the molecular structure, additionally oxidation reactions on the carbon chains (hydroxylation or epoxidation of the double bond) might be expected. In addition, free hydroxy groups (which might result from a metabolic reaction, or which are present in the parent molecule) and introduced epoxides are a potential substrate for conjugation by Phase II enzymes (e.g. UDP-glucuronosyltransferase for hydroxy groups and Glutathione S-transferases for the epoxides). These reactions improve the water solubility of the molecule and enables the excretion via bile or urine. In consideration of the high molecular weight (> 500 Da after conjugation), excretion via bile is more likely.

 

Conclusion

Based on the structural and physico-chemical characteristics of the substance, CAS 8001-79-4 and CAS 97444-44-4 it can be concluded that the substances are likely to absorbed via de oral route, presumably after hydrolysis in the intestine. Intestinal cleavage of the esters groups would result in the release of glycerol and ricinoleic acid. Absorption via de dermal and inhalation route is less likely for all substances. Based on the structural similarity, the substances are expected to result in comparable metabolic profiles and have comparable distribution patterns. Data on CAS 8001-79-4 shows that the metabolism is fast and that therefore there is no risk of bioaccumulation.

 

References:

 

Cosmetic ingredient review 2004:Revised Tentative Report of the Cosmetic Ingredient Review

Expert Panel, Title: Ricinus Communis (Castor) Seed Oil, Hydrogenated Castor Oil, Glyceryl Ricinoleate, Glyceryl Ricinoleate SE, Ricinoleic Acid, Potassium Ricinoleate, Sodium Ricinoleate, Zinc Ricinoleate, Cetyl Ricinoleate, Ethyl Ricinoleate, Glycol Ricinoleate, Isopropyl Ricinoleate, Methyl Ricinoleate, and Octyldodecyl Ricinoleate: December 3, 2004

Cosmetic ingredient review 2004[Ihara-Watanabe et al. (1999)): Effectsof castor oil on lipid metabolismin rats.BiosciBiotechnol Biochem63:595-597.

Cosmetic ingredient review 2004[(Gaginella and Bass, 1978)]: Laxatives: an update on mechanism of action.LifeSol23:1001-1010.

Cosmetic ingredient review 2004[(Stewart and Sinclair, 1945)]:The absence of ricinoleic acid from phospholipids of ratsfedcastor oil. Arch Biochem 8:7.

Cosmetic ingredient review 2004[(Thompson, 1980)]:Laxatives: clinical pharmacology and rational use.Drugs19:49-58.

Cosmetic ingredient review 2004[(Watson and Gordon, 1962)]:Studies on the digestion, absorption and metabolism of castor oil.Biochem Pharmacol11:229-236